Advertisement

The genomics of acute myeloid leukemia in children

  • Shannon E. Conneely
  • Rachel E. RauEmail author
Article

Abstract

Acute myeloid leukemia (AML) is a clinically, morphologically, and genetically heterogeneous disorder. Like many malignancies, the genomic landscape of pediatric AML has been mapped recently through sequencing of large cohorts of patients. Much has been learned about the biology of AML through studies of specific recurrent genetic lesions. Further, genetic lesions have been linked to specific clinical features, response to therapy, and outcome, leading to improvements in risk stratification. Lastly, targeted therapeutic approaches have been developed for the treatment of specific genetic lesions, some of which are already having a positive impact on outcomes. While the advances made based on the discoveries of sequencing studies are significant, much work is left. The biologic, clinical, and prognostic impact of a number of genetic lesions, including several seemingly unique to pediatric patients, remains undefined. While targeted approaches are being explored, for most, the efficacy and tolerability when incorporated into standard therapy is yet to be determined. Furthermore, the challenge of how to study small subpopulations with rare genetic lesions in an already rare disease will have to be considered. In all, while questions and challenges remain, precisely defining the genomic landscape of AML, holds great promise for ultimately leading to improved outcomes for affected patients.

Keywords

Acute myeloid leukemia Pediatric Genomics Risk stratification Targeted therapies 

Notes

Funding information

This work was supported by K08CA201611 from the National Cancer Institute (RR).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    de The, H., Pandolfi, P. P., & Chen, Z. (2017). Acute promyelocytic leukemia: a paradigm for oncoprotein-targeted cure. Cancer Cell, 32(5), 552–560.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    de The, H., & Chen, Z. (2010). Acute promyelocytic leukaemia: novel insights into the mechanisms of cure. Nature Reviews. Cancer, 10(11), 775–783.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    de The, H. (2018). Differentiation therapy revisited. Nature Reviews. Cancer, 18(2), 117–127.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Arber, D. A., Orazi, A., Hasserjian, R., Thiele, J., Borowitz, M. J., le Beau, M. M., Bloomfield, C. D., Cazzola, M., & Vardiman, J. W. (2016). The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood, 127(20), 2391–2405.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Creutzig, U., Zimmermann, M., Reinhardt, D., Rasche, M., von Neuhoff, C., Alpermann, T., Dworzak, M., Perglerová, K., Zemanova, Z., Tchinda, J., Bradtke, J., Thiede, C., & Haferlach, C. (2016). Changes in cytogenetics and molecular genetics in acute myeloid leukemia from childhood to adult age groups. Cancer, 122(24), 3821–3830.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    de The, H., Le Bras, M., & Lallemand-Breitenbach, V. (2012). The cell biology of disease: acute promyelocytic leukemia, arsenic, and PML bodies. The Journal of Cell Biology, 198(1), 11–21.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Ablain, J., Rice, K., Soilihi, H., de Reynies, A., Minucci, S., & de Thé, H. (2014). Activation of a promyelocytic leukemia-tumor protein 53 axis underlies acute promyelocytic leukemia cure. Nature Medicine, 20(2), 167–174.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Vitaliano-Prunier, A., Halftermeyer, J., Ablain, J., de Reynies, A., Peres, L., le Bras, M., Metzger, D., & de Thé, H. (2014). Clearance of PML/RARA-bound promoters suffice to initiate APL differentiation. Blood, 124(25), 3772–3780.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Dos Santos, G. A., Kats, L., & Pandolfi, P. P. (2013). Synergy against PML-RARa: targeting transcription, proteolysis, differentiation, and self-renewal in acute promyelocytic leukemia. The Journal of Experimental Medicine, 210(13), 2793–2802.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Testi, A. M., Pession, A., Diverio, D., Grimwade, D., Gibson, B., de Azevedo, A. C., Moran, L., Leverger, G., Elitzur, S., Hasle, H., van der Werff ten Bosch, J., Smith, O., de Rosa, M., Piciocchi, A., Lo Coco, F., Foà, R., Locatelli, F., & Kaspers, G. J. L. (2018). Risk-adapted treatment of acute promyelocytic leukemia: results from the international consortium for childhood APL. Blood, 132(4), 405–412.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Ortega, J. J., Madero, L., Martín, G., Verdeguer, A., García, P., Parody, R., Fuster, J., Molines, A., Novo, A., Debén, G., Rodríguez, A., Conde, E., de la Serna, J., Allegue, M. J., Capote, F. J., González, J. D., Bolufer, P., González, M., Sanz, M. A., & PETHEMA Group. (2005). Treatment with all-trans retinoic acid and anthracycline monochemotherapy for children with acute promyelocytic leukemia: a multicenter study by the PETHEMA group. Journal of Clinical Oncology, 23(30), 7632–7640.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Kutny, M. A., et al. (2019). Outcome for pediatric acute promyelocytic leukemia patients at Children’s Oncology Group sites on the Leukemia Intergroup Study CALGB 9710 (Alliance). Pediatric Blood & Cancer, 66(3), e27542.CrossRefGoogle Scholar
  13. 13.
    Avvisati, G., Lo Coco, F., Diverio, D., Falda, M., Ferrara, F., Lazzarino, M., Russo, D., Petti, M. C., & Mandelli, F. (1996). AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) pilot study. Blood, 88(4), 1390–1398.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Avvisati, G., Lo-Coco, F., Paoloni, F. P., Petti, M. C., Diverio, D., Vignetti, M., Latagliata, R., Specchia, G., Baccarani, M., di Bona, E., Fioritoni, G., Marmont, F., Rambaldi, A., di Raimondo, F., Kropp, M. G., Pizzolo, G., Pogliani, E. M., Rossi, G., Cantore, N., Nobile, F., Gabbas, A., Ferrara, F., Fazi, P., Amadori, S., Mandelli, F., & GIMEMA, AIEOP, and EORTC Cooperative Groups. (2011). AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood, 117(18), 4716–4725.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Sanz, M. A., Fenaux, P., Tallman, M. S., Estey, E. H., Löwenberg, B., Naoe, T., Lengfelder, E., Döhner, H., Burnett, A. K., Chen, S. J., Mathews, V., Iland, H., Rego, E., Kantarjian, H., Adès, L., Avvisati, G., Montesinos, P., Platzbecker, U., Ravandi, F., Russell, N. H., & Lo-Coco, F. (2019). Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet. Blood, 133(15), 1630–1643.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Kutny, M. A., Alonzo, T. A., Gerbing, R. B., Wang, Y. C., Raimondi, S. C., Hirsch, B. A., Fu, C. H., Meshinchi, S., Gamis, A. S., Feusner, J. H., & Gregory JJ Jr. (2017). Arsenic trioxide consolidation allows anthracycline dose reduction for pediatric patients with acute promyelocytic leukemia: report from the Children’s Oncology Group Phase iii Historically Controlled Trial AAML0631. Journal of Clinical Oncology, 35(26), 3021–3029.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Zhang, L., Zou, Y., Chen, Y., Guo, Y., Yang, W., Chen, X., Wang, S., Liu, X., Ruan, M., Zhang, J., Liu, T., Liu, F., Qi, B., An, W., Ren, Y., Chang, L., & Zhu, X. (2018). Role of cytarabine in paediatric acute promyelocytic leukemia treated with the combination of all-trans retinoic acid and arsenic trioxide: a randomized controlled trial. BMC Cancer, 18(1), 374.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Gill, H., Kumana, C. R., Yim, R., Hwang, Y. Y., Chan, T. S. Y., Yip, S. F., Lee, H. K. K., Mak, V., Lau, J. S. M., Chan, C. C., Kho, B., Wong, R. S. M., Li, W., Lin, S. Y., Lau, C. K., Ip, H. W., Leung, R. Y. Y., Lam, C. C. K., & Kwong, Y. L. (2019). Oral arsenic trioxide incorporation into frontline treatment with all-trans retinoic acid and chemotherapy in newly diagnosed acute promyelocytic leukemia: a 5-year prospective study. Cancer, 125(17), 3001–3012.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Cicconi, L., et al. (2019). Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial. Leukemia.Google Scholar
  20. 20.
    Zhu, H. H., Wu, D. P., du, X., Zhang, X., Liu, L., Ma, J., Shao, Z. H., Ren, H. Y., Hu, J. D., Xu, K. L., Wang, J. W., Song, Y. P., Fang, M. Y., Li, J., Yan, X. Y., & Huang, X. J. (2018). Oral arsenic plus retinoic acid versus intravenous arsenic plus retinoic acid for non-high-risk acute promyelocytic leukaemia: a non-inferiority, randomised phase 3 trial. The Lancet Oncology, 19(7), 871–879.PubMedCrossRefGoogle Scholar
  21. 21.
    Strocchio, L., et al. (2019). Arsenic trioxide and all-trans retinoic acid treatment for childhood acute promyelocytic leukaemia. British Journal of Haematology, 185(2), 360–363.PubMedCrossRefGoogle Scholar
  22. 22.
    Platzbecker, U., Avvisati, G., Cicconi, L., Thiede, C., Paoloni, F., Vignetti, M., Ferrara, F., Divona, M., Albano, F., Efficace, F., Fazi, P., Sborgia, M., di Bona, E., Breccia, M., Borlenghi, E., Cairoli, R., Rambaldi, A., Melillo, L., la Nasa, G., Fiedler, W., Brossart, P., Hertenstein, B., Salih, H. R., Wattad, M., Lübbert, M., Brandts, C. H., Hänel, M., Röllig, C., Schmitz, N., Link, H., Frairia, C., Pogliani, E. M., Fozza, C., D'Arco, A. M., di Renzo, N., Cortelezzi, A., Fabbiano, F., Döhner, K., Ganser, A., Döhner, H., Amadori, S., Mandelli, F., Ehninger, G., Schlenk, R. F., & Lo-Coco, F. (2017). Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. Journal of Clinical Oncology, 35(6), 605–612.PubMedCrossRefGoogle Scholar
  23. 23.
    Lo-Coco, F., di Donato, L., GIMEMA, Schlenk, R. F., & German–Austrian Acute Myeloid Leukemia Study Group and Study Alliance Leukemia. (2016). Targeted therapy alone for acute promyelocytic leukemia. The New England Journal of Medicine, 374(12), 1197–1198.PubMedCrossRefGoogle Scholar
  24. 24.
    Lo-Coco, F., et al. (2013). Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. The New England Journal of Medicine, 369(2), 111–121.PubMedCrossRefGoogle Scholar
  25. 25.
    Burnett, A. K., Russell, N. H., Hills, R. K., Bowen, D., Kell, J., Knapper, S., Morgan, Y. G., Lok, J., Grech, A., Jones, G., Khwaja, A., Friis, L., McMullin, M., Hunter, A., Clark, R. E., Grimwade, D., & UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. (2015). Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. The Lancet Oncology, 16(13), 1295–1305.PubMedCrossRefGoogle Scholar
  26. 26.
    Adams, J., & Nassiri, M. (2015). Acute promyelocytic leukemia: a review and discussion of variant translocations. Archives of Pathology & Laboratory Medicine, 139(10), 1308–1313.CrossRefGoogle Scholar
  27. 27.
    Sainty, D., Liso, V., Cantù-Rajnoldi, A., Head, D., Mozziconacci, M. J., Arnoulet, C., Benattar, L., Fenu, S., Mancini, M., Duchayne, E., Mahon, F. X., Gutierrez, N., Birg, F., Biondi, A., Grimwade, D., Lafage-Pochitaloff, M., Hagemeijer, A., Flandrin, G., Groupe Français d'Hématologie Cellulaire, Groupe Français de Cytogénétique Hématologique, UK Cancer Cytogenetics Group, & BIOMED 1 European Community-Concerted Action "Molecular Cytogenetic Diagnosis in Haematological Malignancies". (2000). A new morphologic classification system for acute promyelocytic leukemia distinguishes cases with underlying PLZF/RARA gene rearrangements. Blood, 96(4), 1287–1296.PubMedGoogle Scholar
  28. 28.
    Osumi, T., Tsujimoto, S. I., Tamura, M., Uchiyama, M., Nakabayashi, K., Okamura, K., Yoshida, M., Tomizawa, D., Watanabe, A., Takahashi, H., Hori, T., Yamamoto, S., Hamamoto, K., Migita, M., Ogata-Kawata, H., Uchiyama, T., Kizawa, H., Ueno-Yokohata, H., Shirai, R., Seki, M., Ohki, K., Takita, J., Inukai, T., Ogawa, S., Kitamura, T., Matsumoto, K., Hata, K., Kiyokawa, N., Goyama, S., & Kato, M. (2018). Recurrent RARB translocations in acute promyelocytic leukemia lacking RARA translocation. Cancer Research, 78(16), 4452–4458.PubMedCrossRefGoogle Scholar
  29. 29.
    Qiu, J. J., et al. (2015). Critical role of retinoid/rexinoid signaling in mediating transformation and therapeutic response of NUP98-RARG leukemia. Leukemia, 29(5), 1153–1162.PubMedCrossRefGoogle Scholar
  30. 30.
    Harrison, C. J., Hills, R. K., Moorman, A. V., Grimwade, D. J., Hann, I., Webb, D. K., Wheatley, K., de Graaf, S. S., van den Berg, E., Burnett, A. K., & Gibson, B. E. (2010). Cytogenetics of childhood acute myeloid leukemia: United Kingdom Medical Research Council treatment trials AML 10 and 12. Journal of Clinical Oncology, 28(16), 2674–2681.PubMedCrossRefGoogle Scholar
  31. 31.
    von Neuhoff, C., et al. (2010). Prognostic impact of specific chromosomal aberrations in a large group of pediatric patients with acute myeloid leukemia treated uniformly according to trial AML-BFM 98. Journal of Clinical Oncology, 28(16), 2682–2689.CrossRefGoogle Scholar
  32. 32.
    Bolouri, H., Farrar, J. E., Triche T Jr, Ries, R. E., Lim, E. L., Alonzo, T. A., Ma, Y., Moore, R., Mungall, A. J., Marra, M. A., Zhang, J., Ma, X., Liu, Y., Liu, Y., Auvil, J. M. G., Davidsen, T. M., Gesuwan, P., Hermida, L. C., Salhia, B., Capone, S., Ramsingh, G., Zwaan, C. M., Noort, S., Piccolo, S. R., Kolb, E. A., Gamis, A. S., Smith, M. A., Gerhard, D. S., & Meshinchi, S. (2018). The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Nature Medicine, 24(1), 103–112.PubMedCrossRefGoogle Scholar
  33. 33.
    Klein, K., et al. (2015). Clinical impact of additional cytogenetic aberrations, cKIT and RAS mutations, and treatment elements in pediatric t(8;21)-AML: results from an International Retrospective Study by the International Berlin-Frankfurt-Munster Study Group. Journal of Clinical Oncology, 33(36), 4247–4258.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Tarlock, K., Alonzo, T. A., Wang, Y. C., Gerbing, R. B., Ries, R., Loken, M. R., Pardo, L., Hylkema, T., Joaquin, J., Sarukkai, L., Raimondi, S. C., Hirsch, B., Sung, L., Aplenc, R., Bernstein, I., Gamis, A. S., Meshinchi, S., & Pollard, J. A. (2019). Functional properties of KIT mutations are associated with differential clinical outcomes and response to targeted therapeutics in CBF acute myeloid leukemia. Clinical Cancer Research, 25(16), 5038–5048.PubMedCrossRefGoogle Scholar
  35. 35.
    Grimwade, D., Walker, H., Oliver, F., Wheatley, K., Harrison, C., Harrison, G., Rees, J., Hann, I., Stevens, R., Burnett, A., & Goldstone, A. (1998). The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood, 92(7), 2322–2333.PubMedCrossRefGoogle Scholar
  36. 36.
    Downing, J. R. (2003). The core-binding factor leukemias: lessons learned from murine models. Current Opinion in Genetics & Development, 13(1), 48–54.CrossRefGoogle Scholar
  37. 37.
    Speck, N. A., & Gilliland, D. G. (2002). Core-binding factors in haematopoiesis and leukaemia. Nature Reviews. Cancer, 2(7), 502–513.PubMedCrossRefGoogle Scholar
  38. 38.
    Eghtedar, A., Borthakur, G., Ravandi, F., Jabbour, E., Cortes, J., Pierce, S., Kantarjian, H., & Garcia-Manero, G. (2012). Characteristics of translocation (16;16)(p13;q22) acute myeloid leukemia. American Journal of Hematology, 87(3), 317–318.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Adya, N., et al. (1998). The leukemic protein core binding factor beta (CBFbeta)-smooth-muscle myosin heavy chain sequesters CBFalpha2 into cytoskeletal filaments and aggregates. Molecular and Cellular Biology, 18(12), 7432–7443.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Marcucci, G., Mrózek, K., Ruppert, A. S., Maharry, K., Kolitz, J. E., Moore, J. O., Mayer, R. J., Pettenati, M. J., Powell, B. L., Edwards, C. G., Sterling, L. J., Vardiman, J. W., Schiffer, C. A., Carroll, A. J., Larson, R. A., & Bloomfield, C. D. (2005). Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B study. Journal of Clinical Oncology, 23(24), 5705–5717.PubMedCrossRefGoogle Scholar
  41. 41.
    Moorman, A. V., Ensor, H. M., Richards, S. M., Chilton, L., Schwab, C., Kinsey, S. E., Vora, A., Mitchell, C. D., & Harrison, C. J. (2010). Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial. The Lancet Oncology, 11(5), 429–438.PubMedCrossRefGoogle Scholar
  42. 42.
    Loh, M. L., Devidas, E. R. M., Dai, Y., Borowitz, M. J., Carroll, A. J., Chen, I.-M., Gastier-Foster, J. M., Friedmann, A. M., Harvey, R. C., Heerema, N. A., Larsen, E., Li, Y., Maloney, K. W., Mattano Jr., L. A., Mullighan, C. G., Rabin, K. R., Reshmi, S. C., Roberts, K. G., Willman, C. L., Wood, B. L., Zweidler-McKay, P., Zhang, J., Winick, N., Hunger, S., & Carroll, W. L. (2016). Outcomes of Children, Adolescents, and Young Adults with Acute Lymphoblastic Leukemia Based on Blast Genotype at Diagnosis: A Report from the Children's Oncology Group. Blood, 128(22), 451.Google Scholar
  43. 43.
    Matlawska-Wasowska, K., Kang, H., Devidas, M., Wen, J., Harvey, R. C., Nickl, C. K., Ness, S. A., Rusch, M., Li, Y., Onozawa, M., Martinez, C., Wood, B. L., Asselin, B. L., Chen, I. M., Roberts, K. G., Baruchel, A., Soulier, J., Dombret, H., Zhang, J., Larson, R. S., Raetz, E. A., Carroll, W. L., Winick, N. J., Aplan, P. D., Loh, M. L., Mullighan, C. G., Hunger, S. P., Heerema, N. A., Carroll, A. J., Dunsmore, K. P., & Winter, S. S. (2016). MLL rearrangements impact outcome in HOXA-deregulated T-lineage acute lymphoblastic leukemia: a Children’s Oncology Group Study. Leukemia, 30(9), 1909–1912.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Hilden, J. M., Dinndorf, P. A., Meerbaum, S. O., Sather, H., Villaluna, D., Heerema, N. A., McGlennen, R., Smith, F. O., Woods, W. G., Salzer, W. L., Johnstone, H. S., Dreyer, Z., Reaman, G. H., & Children's Oncology Group. (2006). Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children’s Oncology Group. Blood, 108(2), 441–451.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Winters, A. C., & Bernt, K. M. (2017). MLL-rearranged leukemias-an update on science and clinical approaches. Frontiers in Pediatrics, 5, 4.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Balgobind, B. V., Raimondi, S. C., Harbott, J., Zimmermann, M., Alonzo, T. A., Auvrignon, A., Beverloo, H. B., Chang, M., Creutzig, U., Dworzak, M. N., Forestier, E., Gibson, B., Hasle, H., Harrison, C. J., Heerema, N. A., Kaspers, G. J., Leszl, A., Litvinko, N., Nigro, L. L., Morimoto, A., Perot, C., Pieters, R., Reinhardt, D., Rubnitz, J. E., Smith, F. O., Stary, J., Stasevich, I., Strehl, S., Taga, T., Tomizawa, D., Webb, D., Zemanova, Z., Zwaan, C. M., & van den Heuvel-Eibrink, M. (2009). Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood, 114(12), 2489–2496.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Papaemmanuil, E., Gerstung, M., Bullinger, L., Gaidzik, V. I., Paschka, P., Roberts, N. D., Potter, N. E., Heuser, M., Thol, F., Bolli, N., Gundem, G., van Loo, P., Martincorena, I., Ganly, P., Mudie, L., McLaren, S., O'Meara, S., Raine, K., Jones, D. R., Teague, J. W., Butler, A. P., Greaves, M. F., Ganser, A., Döhner, K., Schlenk, R. F., Döhner, H., & Campbell, P. J. (2016). Genomic classification and prognosis in acute myeloid leukemia. The New England Journal of Medicine, 374(23), 2209–2221.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Meyer, C., Burmeister, T., Gröger, D., Tsaur, G., Fechina, L., Renneville, A., Sutton, R., Venn, N. C., Emerenciano, M., Pombo-de-Oliveira, M. S., Barbieri Blunck, C., Almeida Lopes, B., Zuna, J., Trka, J., Ballerini, P., Lapillonne, H., de Braekeleer, M., Cazzaniga, G., Corral Abascal, L., van der Velden, V., Delabesse, E., Park, T. S., Oh, S. H., Silva, M. L. M., Lund-Aho, T., Juvonen, V., Moore, A. S., Heidenreich, O., Vormoor, J., Zerkalenkova, E., Olshanskaya, Y., Bueno, C., Menendez, P., Teigler-Schlegel, A., Zur Stadt, U., Lentes, J., Göhring, G., Kustanovich, A., Aleinikova, O., Schäfer, B. W., Kubetzko, S., Madsen, H. O., Gruhn, B., Duarte, X., Gameiro, P., Lippert, E., Bidet, A., Cayuela, J. M., Clappier, E., Alonso, C. N., Zwaan, C. M., van den Heuvel-Eibrink, M., Izraeli, S., Trakhtenbrot, L., Archer, P., Hancock, J., Möricke, A., Alten, J., Schrappe, M., Stanulla, M., Strehl, S., Attarbaschi, A., Dworzak, M., Haas, O. A., Panzer-Grümayer, R., Sedék, L., Szczepański, T., Caye, A., Suarez, L., Cavé, H., & Marschalek, R. (2018). The MLL recombinome of acute leukemias in 2017. Leukemia, 32(2), 273–284.PubMedCrossRefGoogle Scholar
  49. 49.
    Spencer, D. H., Young, M. A., Lamprecht, T. L., Helton, N. M., Fulton, R., O'Laughlin, M., Fronick, C., Magrini, V., Demeter, R. T., Miller, C. A., Klco, J. M., Wilson, R. K., & Ley, T. J. (2015). Epigenomic analysis of the HOX gene loci reveals mechanisms that may control canonical expression patterns in AML and normal hematopoietic cells. Leukemia, 29(6), 1279–1289.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Kawagoe, H., Humphries, R. K., Blair, A., Sutherland, H. J., & Hogge, D. E. (1999). Expression of HOX genes, HOX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells. Leukemia, 13(5), 687–698.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Bernt, K. M., Zhu, N., Sinha, A. U., Vempati, S., Faber, J., Krivtsov, A. V., Feng, Z., Punt, N., Daigle, A., Bullinger, L., Pollock, R. M., Richon, V. M., Kung, A. L., & Armstrong, S. A. (2011). MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell, 20(1), 66–78.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Daigle, S. R., Olhava, E. J., Therkelsen, C. A., Basavapathruni, A., Jin, L., Boriack-Sjodin, P. A., Allain, C. J., Klaus, C. R., Raimondi, A., Scott, M. P., Waters, N. J., Chesworth, R., Moyer, M. P., Copeland, R. A., Richon, V. M., & Pollock, R. M. (2013). Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood, 122(6), 1017–1025.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Neerav Shukla, C. W., O’Brien, M. M., Silverman, L. B., Brown, P., Cooper, T. M., Thomson, B., Blakemore, S. J., Daigle, S., Suttle, B., Waters, N. J., Krivstov, A. V., Armstrong, S. A., Ho, P. T., & Gore, L. (2016). Final Report of Phase 1 Study of the DOT1L Inhibitor, Pinometostat (EPZ-5676), in Children with Relapsed or Refractory MLL-r Acute Leukemia. Blood, 128(22), 1.CrossRefGoogle Scholar
  54. 54.
    He, S., Malik, B., Borkin, D., Miao, H., Shukla, S., Kempinska, K., Purohit, T., Wang, J., Chen, L., Parkin, B., Malek, S. N., Danet-Desnoyers, G., Muntean, A. G., Cierpicki, T., & Grembecka, J. (2016). Menin-MLL inhibitors block oncogenic transformation by MLL-fusion proteins in a fusion partner-independent manner. Leukemia, 30(2), 508–513.PubMedCrossRefGoogle Scholar
  55. 55.
    Danis, E., et al. (2015). Inactivation of Eed impedes MLL-AF9-mediated leukemogenesis through Cdkn2a-dependent and Cdkn2a-independent mechanisms in a murine model. Experimental Hematology, 43(11), 930–935 e6.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Kaushik, S., Liu, F., Veazey, K. J., Gao, G., Das, P., Neves, L. F., Lin, K., Zhong, Y., Lu, Y., Giuliani, V., Bedford, M. T., Nimer, S. D., & Santos, M. A. (2018). Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML. Leukemia, 32(2), 499–509.PubMedCrossRefGoogle Scholar
  57. 57.
    Feng, Z., et al. (2016). Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia. Journal of Hematology & Oncology, 9, 24.CrossRefGoogle Scholar
  58. 58.
    Fung, J. J., et al. (2015). Registered report: inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukemia. Elife, 4.Google Scholar
  59. 59.
    Schafer, E., Irizarry, R., Negi, S., McIntyre, E., Small, D., Figueroa, M. E., Melnick, A., & Brown, P. (2010). Promoter hypermethylation in MLL-r infant acute lymphoblastic leukemia: biology and therapeutic targeting. Blood, 115(23), 4798–4809.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Stumpel, D. J., Schotte, D., Lange-Turenhout, E. A., Schneider, P., Seslija, L., de Menezes, R. X., Marquez, V. E., Pieters, R., den Boer, M., & Stam, R. W. (2011). Hypermethylation of specific microRNA genes in MLL-rearranged infant acute lymphoblastic leukemia: major matters at a micro scale. Leukemia, 25(3), 429–439.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Tonelli, R., et al. (2006). G1 cell-cycle arrest and apoptosis by histone deacetylase inhibition in MLL-AF9 acute myeloid leukemia cells is p21 dependent and MLL-AF9 independent. Leukemia, 20(7), 1307–1310.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Liu, J., et al. (2015). Targeting the ubiquitin pathway for cancer treatment. Biochimica et Biophysica Acta, 1855(1), 50–60.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Franks, T. M., et al. (2017). Nup98 recruits the Wdr82-Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells. Genes & Development, 31(22), 2222–2234.CrossRefGoogle Scholar
  64. 64.
    Pascual-Garcia, P., Jeong, J., & Capelson, M. (2014). Nucleoporin Nup98 associates with Trx/MLL and NSL histone-modifying complexes and regulates Hox gene expression. Cell Reports, 9(5), 1981.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Pascual-Garcia, P., Jeong, J., & Capelson, M. (2014). Nucleoporin Nup98 associates with Trx/MLL and NSL histone-modifying complexes and regulates Hox gene expression. Cell Reports, 9(2), 433–442.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Struski, S., Lagarde, S., Bories, P., Puiseux, C., Prade, N., Cuccuini, W., Pages, M. P., Bidet, A., Gervais, C., Lafage-Pochitaloff, M., Roche-Lestienne, C., Barin, C., Penther, D., Nadal, N., Radford-Weiss, I., Collonge-Rame, M. A., Gaillard, B., Mugneret, F., Lefebvre, C., Bart-Delabesse, E., Petit, A., Leverger, G., Broccardo, C., Luquet, I., Pasquet, M., & Delabesse, E. (2017). NUP98 is rearranged in 3.8% of pediatric AML forming a clinical and molecular homogenous group with a poor prognosis. Leukemia, 31(3), 565–572.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Shiba, N., Yoshida, K., Hara, Y., Yamato, G., Shiraishi, Y., Matsuo, H., Okuno, Y., Chiba, K., Tanaka, H., Kaburagi, T., Takeuchi, M., Ohki, K., Sanada, M., Okubo, J., Tomizawa, D., Taki, T., Shimada, A., Sotomatsu, M., Horibe, K., Taga, T., Adachi, S., Tawa, A., Miyano, S., Ogawa, S., & Hayashi, Y. (2019). Transcriptome analysis offers a comprehensive illustration of the genetic background of pediatric acute myeloid leukemia. Blood Adv, 3(20), 3157–3169.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Hollink, I. H., van den Heuvel-Eibrink, M., Arentsen-Peters, S. T., Pratcorona, M., Abbas, S., Kuipers, J. E., van Galen, J., Beverloo, H. B., Sonneveld, E., Kaspers, G. J., Trka, J., Baruchel, A., Zimmermann, M., Creutzig, U., Reinhardt, D., Pieters, R., Valk, P. J., & Zwaan, C. M. (2011). NUP98/NSD1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct HOX gene expression pattern. Blood, 118(13), 3645–3656.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Bisio, V., Zampini, M., Tregnago, C., Manara, E., Salsi, V., di Meglio, A., Masetti, R., Togni, M., di Giacomo, D., Minuzzo, S., Leszl, A., Zappavigna, V., Rondelli, R., Mecucci, C., Pession, A., Locatelli, F., Basso, G., & Pigazzi, M. (2017). NUP98-fusion transcripts characterize different biological entities within acute myeloid leukemia: a report from the AIEOP-AML group. Leukemia, 31(4), 974–977.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Calvo, K. R., et al. (2002). Nup98-HoxA9 immortalizes myeloid progenitors, enforces expression of Hoxa9, Hoxa7 and Meis1, and alters cytokine-specific responses in a manner similar to that induced by retroviral co-expression of Hoxa9 and Meis1. Oncogene, 21(27), 4247–4256.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Pineault, N., et al. (2003). Induction of acute myeloid leukemia in mice by the human leukemia-specific fusion gene NUP98-HOXD13 in concert with Meis1. Blood, 101(11), 4529–4538.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Wang, G. G., Cai, L., Pasillas, M. P., & Kamps, M. P. (2007). NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nature Cell Biology, 9(7), 804–812.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Wang, G. G., Song, J., Wang, Z., Dormann, H. L., Casadio, F., Li, H., Luo, J. L., Patel, D. J., & Allis, C. D. (2009). Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger. Nature, 459(7248), 847–851.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    de Rooij, J. D., Branstetter, C., Ma, J., Li, Y., Walsh, M. P., Cheng, J., Obulkasim, A., Dang, J., Easton, J., Verboon, L. J., Mulder, H. L., Zimmermann, M., Koss, C., Gupta, P., Edmonson, M., Rusch, M., Lim, J. Y., Reinhardt, K., Pigazzi, M., Song, G., Yeoh, A. E., Shih, L. Y., Liang, D. C., Halene, S., Krause, D. S., Zhang, J., Downing, J. R., Locatelli, F., Reinhardt, D., van den Heuvel-Eibrink, M., Zwaan, C. M., Fornerod, M., & Gruber, T. A. (2017). Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes. Nature Genetics, 49(3), 451–456.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Iacobucci, I., Wen, J., Meggendorfer, M., Choi, J. K., Shi, L., Pounds, S. B., Carmichael, C. L., Masih, K. E., Morris, S. M., Lindsley, R. C., Janke, L. J., Alexander, T. B., Song, G., Qu, C., Li, Y., Payne-Turner, D., Tomizawa, D., Kiyokawa, N., Valentine, M., Valentine, V., Basso, G., Locatelli, F., Enemark, E. J., Kham, S. K. Y., Yeoh, A. E. J., Ma, X., Zhou, X., Sioson, E., Rusch, M., Ries, R. E., Stieglitz, E., Hunger, S. P., Wei, A. H., To, L. B., Lewis, I. D., D'Andrea, R. J., Kile, B. T., Brown, A. L., Scott, H. S., Hahn, C. N., Marlton, P., Pei, D., Cheng, C., Loh, M. L., Ebert, B. L., Meshinchi, S., Haferlach, T., & Mullighan, C. G. (2019). Genomic subtyping and therapeutic targeting of acute erythroleukemia. Nature Genetics, 51(4), 694–704.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Xu, H., Valerio, D. G., Eisold, M. E., Sinha, A., Koche, R. P., Hu, W., Chen, C. W., Chu, S. H., Brien, G. L., Park, C. Y., Hsieh, J. J., Ernst, P., & Armstrong, S. A. (2016). NUP98 fusion proteins interact with the NSL and MLL1 complexes to drive leukemogenesis. Cancer Cell, 30(6), 863–878.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Gough, S. M., Lee, F., Yang, F., Walker, R. L., Zhu, Y. J., Pineda, M., Onozawa, M., Chung, Y. J., Bilke, S., Wagner, E. K., Denu, J. M., Ning, Y., Xu, B., Wang, G. G., Meltzer, P. S., & Aplan, P. D. (2014). NUP98-PHF23 is a chromatin-modifying oncoprotein that causes a wide array of leukemias sensitive to inhibition of PHD histone reader function. Cancer Discovery, 4(5), 564–577.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Katsumoto, T., Aikawa, Y., Iwama, A., Ueda, S., Ichikawa, H., Ochiya, T., & Kitabayashi, I. (2006). MOZ is essential for maintenance of hematopoietic stem cells. Genes & Development, 20(10), 1321–1330.CrossRefGoogle Scholar
  79. 79.
    Katsumoto, T., Yoshida, N., & Kitabayashi, I. (2008). Roles of the histone acetyltransferase monocytic leukemia zinc finger protein in normal and malignant hematopoiesis. Cancer Science, 99(8), 1523–1527.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Camos, M., et al. (2006). Gene expression profiling of acute myeloid leukemia with translocation t(8;16)(p11;p13) and MYST3-CREBBP rearrangement reveals a distinctive signature with a specific pattern of HOX gene expression. Cancer Research, 66(14), 6947–6954.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Classen, C. F., Behnisch, W., Reinhardt, D., Koenig, M., Möller, P., & Debatin, K. M. (2005). Spontaneous complete and sustained remission of a rearrangement CBP (16p13)-positive disseminated congenital myelosarcoma. Annals of Hematology, 84(4), 274–275.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Wu, X., Sulavik, D., Roulston, D., & Lim, M. S. (2011). Spontaneous remission of congenital acute myeloid leukemia with t(8;16)(p11;13). Pediatric Blood & Cancer, 56(2), 331–332.Google Scholar
  83. 83.
    von Bergh, A. R., et al. (2006). High incidence of t(7;12)(q36;p13) in infant AML but not in infant ALL, with a dismal outcome and ectopic expression of HLXB9. Genes, Chromosomes & Cancer, 45(8), 731–739.CrossRefGoogle Scholar
  84. 84.
    Tosi, S., et al. (2015). Paediatric acute myeloid leukaemia with the t(7;12)(q36;p13) rearrangement: a review of the biological and clinical management aspects. Biomarker Research, 3, 21.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Espersen, A. D. L., Noren-Nyström, U., Abrahamsson, J., Ha, S. Y., Pronk, C. J., Jahnukainen, K., Jónsson, Ó. G., Lausen, B., Palle, J., Zeller, B., Palmqvist, L., & Hasle, H. (2018). Acute myeloid leukemia (AML) with t(7;12)(q36;p13) is associated with infancy and trisomy 19: Data from Nordic Society for Pediatric Hematology and Oncology (NOPHO-AML) and review of the literature. Genes, Chromosomes & Cancer, 57(7), 359–365.CrossRefGoogle Scholar
  86. 86.
    Masetti, R., Bertuccio, S. N., Pession, A., & Locatelli, F. (2019). CBFA2T3-GLIS2-positive acute myeloid leukaemia. A peculiar paediatric entity. British Journal of Haematology, 184(3), 337–347.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Chyla, B. J., Moreno-Miralles, I., Steapleton, M. A., Thompson, M. A., Bhaskara, S., Engel, M., & Hiebert, S. W. (2008). Deletion of Mtg16, a target of t(16;21), alters hematopoietic progenitor cell proliferation and lineage allocation. Molecular and Cellular Biology, 28(20), 6234–6247.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Fischer, M. A., et al. (2012). Myeloid translocation gene 16 is required for maintenance of haematopoietic stem cell quiescence. The EMBO Journal, 31(6), 1494–1505.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Thirant, C., Lopez, C., Malinge, S., & Mercher, T. (2017). Molecular pathways driven by ETO2-GLIS2 in aggressive pediatric leukemia. Molecular & Cellular Oncology, 4(6), e1345351.CrossRefGoogle Scholar
  90. 90.
    Thirant, C., et al. (2017). ETO2-GLIS2 hijacks transcriptional complexes to drive cellular identity and self-renewal in pediatric acute megakaryoblastic leukemia. Cancer Cell, 31(3), 452–465.PubMedCrossRefGoogle Scholar
  91. 91.
    Inaba, H., Zhou, Y., Abla, O., Adachi, S., Auvrignon, A., Beverloo, H. B., de Bont, E., Chang, T. T., Creutzig, U., Dworzak, M., Elitzur, S., Fynn, A., Forestier, E., Hasle, H., Liang, D. C., Lee, V., Locatelli, F., Masetti, R., de Moerloose, B., Reinhardt, D., Rodriguez, L., van Roy, N., Shen, S., Taga, T., Tomizawa, D., Yeoh, A. E., Zimmermann, M., & Raimondi, S. C. (2015). Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study. Blood, 126(13), 1575–1584.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Hara, Y., Shiba, N., Ohki, K., Tabuchi, K., Yamato, G., Park, M. J., Tomizawa, D., Kinoshita, A., Shimada, A., Arakawa, H., Saito, A. M., Kiyokawa, N., Tawa, A., Horibe, K., Taga, T., Adachi, S., Taki, T., & Hayashi, Y. (2017). Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non-Down syndrome. Genes, Chromosomes & Cancer, 56(5), 394–404.CrossRefGoogle Scholar
  93. 93.
    Masetti, R., Pigazzi, M., Togni, M., Astolfi, A., Indio, V., Manara, E., Casadio, R., Pession, A., Basso, G., & Locatelli, F. (2013). CBFA2T3-GLIS2 fusion transcript is a novel common feature in pediatric, cytogenetically normal AML, not restricted to FAB M7 subtype. Blood, 121(17), 3469–3472.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    O'Brien, M. M., Cao, X., Pounds, S., Dahl, G. V., Raimondi, S. C., Lacayo, N. J., Taub, J., Chang, M., Weinstein, H. J., Ravindranath, Y., Inaba, H., Campana, D., Pui, C. H., & Rubnitz, J. E. (2013). Prognostic features in acute megakaryoblastic leukemia in children without Down syndrome: a report from the AML02 multicenter trial and the Children’s Oncology Group Study POG 9421. Leukemia, 27(3), 731–734.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Masetti, R., Bertuccio, S. N., Astolfi, A., Chiarini, F., Lonetti, A., Indio, V., de Luca, M., Bandini, J., Serravalle, S., Franzoni, M., Pigazzi, M., Martelli, A. M., Basso, G., Locatelli, F., & Pession, A. (2017). Hh/Gli antagonist in acute myeloid leukemia with CBFA2T3-GLIS2 fusion gene. Journal of Hematology & Oncology, 10(1), 26.CrossRefGoogle Scholar
  96. 96.
    Creutzig, U., Reinhardt, D., Diekamp, S., Dworzak, M., Stary, J., & Zimmermann, M. (2005). AML patients with down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia, 19(8), 1355–1360.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Gamis, A. S. (2005). Acute myeloid leukemia and down syndrome evolution of modern therapy--state of the art review. Pediatric Blood & Cancer, 44(1), 13–20.CrossRefGoogle Scholar
  98. 98.
    Hitzler, J. K., & Zipursky, A. (2005). Origins of leukaemia in children with down syndrome. Nature Reviews. Cancer, 5(1), 11–20.PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Rao, A., Hills, R. K., Stiller, C., Gibson, B. E., de Graaf, S. S., Hann, I. M., O'Marcaigh, A., Wheatley, K., & Webb, D. K. (2006). Treatment for myeloid leukaemia of Down syndrome: population-based experience in the UK and results from the Medical Research Council AML 10 and AML 12 trials. British Journal of Haematology, 132(5), 576–583.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Qin, H., Malek, S., Cowell, J. K., & Ren, M. (2016). Transformation of human CD34+ hematopoietic progenitor cells with DEK-NUP214 induces AML in an immunocompromised mouse model. Oncogene, 35(43), 5686–5691.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Mendes, A., & Fahrenkrog, B. (2019). NUP214 in Leukemia: It's More than Transport. Cells, 8(1).Google Scholar
  102. 102.
    Sandahl, J. D., Coenen, E. A., Forestier, E., Harbott, J., Johansson, B., Kerndrup, G., Adachi, S., Auvrignon, A., Beverloo, H. B., Cayuela, J. M., Chilton, L., Fornerod, M., de Haas, V., Harrison, C. J., Inaba, H., Kaspers, G. J., Liang, D. C., Locatelli, F., Masetti, R., Perot, C., Raimondi, S. C., Reinhardt, K., Tomizawa, D., von Neuhoff, N., Zecca, M., Zwaan, C. M., van den Heuvel-Eibrink, M., & Hasle, H. (2014). T(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients. Haematologica, 99(5), 865–872.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Tarlock, K., Alonzo, T. A., Moraleda, P. P., Gerbing, R. B., Raimondi, S. C., Hirsch, B. A., Ravindranath, Y., Lange, B., Woods, W. G., Gamis, A. S., & Meshinchi, S. (2014). Acute myeloid leukaemia (AML) with t(6;9)(p23;q34) is associated with poor outcome in childhood AML regardless of FLT3-ITD status: a report from the Children’s Oncology Group. British Journal of Haematology, 166(2), 254–259.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Groschel, S., et al. (2014). A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell, 157(2), 369–381.PubMedCrossRefGoogle Scholar
  105. 105.
    Meshinchi, S., Alonzo, T. A., Stirewalt, D. L., Zwaan, M., Zimmerman, M., Reinhardt, D., Kaspers, G. J., Heerema, N. A., Gerbing, R., Lange, B. J., & Radich, J. P. (2006). Clinical implications of FLT3 mutations in pediatric AML. Blood, 108(12), 3654–3661.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Pratz, K. W., & Levis, M. (2017). How I treat FLT3-mutated AML. Blood, 129(5), 565–571.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Sexauer, A. N., & Tasian, S. K. (2017). Targeting FLT3 signaling in childhood acute myeloid leukemia. Frontiers in Pediatrics, 5, 248.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Thiede, C., et al. (2002). Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood, 99(12), 4326–4335.CrossRefGoogle Scholar
  109. 109.
    Zwaan, C. M., et al. (2003). FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance. Blood, 102(7), 2387–2394.PubMedCrossRefGoogle Scholar
  110. 110.
    Liang, D. C., et al. (2002). Clinical relevance of internal tandem duplication of the FLT3 gene in childhood acute myeloid leukemia. Cancer, 94(12), 3292–3298.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Gilliland, D. G., & Griffin, J. D. (2002). The roles of FLT3 in hematopoiesis and leukemia. Blood, 100(5), 1532–1542.CrossRefGoogle Scholar
  112. 112.
    Small, D., Levenstein, M., Kim, E., Carow, C., Amin, S., Rockwell, P., Witte, L., Burrow, C., Ratajczak, M. Z., & Gewirtz, A. M. (1994). STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proceedings of the National Academy of Sciences of the United States of America, 91(2), 459–463.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Iwama, A., Okano, K., Sudo, T., Matsuda, Y., & Suda, T. (1994). Molecular cloning of a novel receptor tyrosine kinase gene, STK, derived from enriched hematopoietic stem cells. Blood, 83(11), 3160–3169.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Matthews, W., Jordan, C. T., Wiegand, G. W., Pardoll, D., & Lemischka, I. R. (1991). A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell, 65(7), 1143–1152.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Levis, M., & Small, D. (2003). FLT3: ITDoes matter in leukemia. Leukemia, 17(9), 1738–1752.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Tarlock, K., Hylkema, M. E. H. T., Ries, R., Farrar, J. E., Auvil, J. G., Gerhard, D. S., Smith, M. A., Davidsen, T. M., Gesuwan, P., Hermida, L. C., Marra, M. A., Mungall, A. J., Mungall, K., Ma, Y., Zong, S., Long, W., Boggon, T., Alonzo, T. A., Kolb, E. A., Gamis, A. S., & Meshinchi, S. (2015). Discovery and Functional Validation of Novel Pediatric Specific FLT3 Activating Mutations in Acute Myeloid Leukemia: Results from the COG/NCI Target Initiative. Blood, 126(23), 1.CrossRefGoogle Scholar
  117. 117.
    Hollink, I. H., Zwaan, C. M., Zimmermann, M., Arentsen-Peters, T. C., Pieters, R., Cloos, J., Kaspers, G. J., de Graaf, S. S., Harbott, J., Creutzig, U., Reinhardt, D., van den Heuvel-Eibrink, M., & Thiede, C. (2009). Favorable prognostic impact of NPM1 gene mutations in childhood acute myeloid leukemia, with emphasis on cytogenetically normal AML. Leukemia, 23(2), 262–270.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Bornhauser, M., et al. (2007). Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML. Blood, 109(5), 2264–2265 author reply 2265.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    DeZern, A. E., et al. (2011). Role of allogeneic transplantation for FLT3/ITD acute myeloid leukemia: outcomes from 133 consecutive newly diagnosed patients from a single institution. Biology of Blood and Marrow Transplantation, 17(9), 1404–1409.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Daver, N., Schlenk, R. F., Russell, N. H., & Levis, M. J. (2019). Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia, 33(2), 299–312.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Grunwald, M. R., & Levis, M. J. (2015). FLT3 tyrosine kinase inhibition as a paradigm for targeted drug development in acute myeloid leukemia. Seminars in Hematology, 52(3), 193–199.PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Stone, R. M., Mandrekar, S. J., Sanford, B. L., Laumann, K., Geyer, S., Bloomfield, C. D., Thiede, C., Prior, T. W., Döhner, K., Marcucci, G., Lo-Coco, F., Klisovic, R. B., Wei, A., Sierra, J., Sanz, M. A., Brandwein, J. M., de Witte, T., Niederwieser, D., Appelbaum, F. R., Medeiros, B. C., Tallman, M. S., Krauter, J., Schlenk, R. F., Ganser, A., Serve, H., Ehninger, G., Amadori, S., Larson, R. A., & Döhner, H. (2017). Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. The New England Journal of Medicine, 377(5), 454–464.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Levis, M. (2017). Midostaurin approved for FLT3-mutated AML. Blood, 129(26), 3403–3406.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Stone, R. M., Manley, P. W., Larson, R. A., & Capdeville, R. (2018). Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. Blood Adv, 2(4), 444–453.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    McMahon, C. M., et al. (2019). Gilteritinib induces differentiation in relapsed and refractory FLT3-mutated acute myeloid leukemia. Blood Adv, 3(10), 1581–1585.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    McMahon, C. M., & Perl, A. E. (2019). Gilteritinib for the treatment of relapsed and/or refractory FLT3-mutated acute myeloid leukemia. Expert Review of Clinical Pharmacology, 12(9), 841–849.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Perl, A. E., Martinelli, G., Cortes, J. E., Neubauer, A., Berman, E., Paolini, S., Montesinos, P., Baer, M. R., Larson, R. A., Ustun, C., Fabbiano, F., Erba, H. P., di Stasi, A., Stuart, R., Olin, R., Kasner, M., Ciceri, F., Chou, W. C., Podoltsev, N., Recher, C., Yokoyama, H., Hosono, N., Yoon, S. S., Lee, J. H., Pardee, T., Fathi, A. T., Liu, C., Hasabou, N., Liu, X., Bahceci, E., & Levis, M. J. (2019). Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. The New England Journal of Medicine, 381(18), 1728–1740.PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Inaba, H., Rubnitz, J. E., Coustan-Smith, E., Li, L., Furmanski, B. D., Mascara, G. P., Heym, K. M., Christensen, R., Onciu, M., Shurtleff, S. A., Pounds, S. B., Pui, C. H., Ribeiro, R. C., Campana, D., & Baker, S. D. (2011). Phase I pharmacokinetic and pharmacodynamic study of the multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in pediatric relapsed/refractory leukemia. Journal of Clinical Oncology, 29(24), 3293–3300.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Widemann, B. C., et al. (2012). A phase I trial and pharmacokinetic study of sorafenib in children with refractory solid tumors or leukemias: a Children’s Oncology Group phase I consortium report. Clinical Cancer Research, 18(21), 6011–6022.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Galanis, A., et al. (2014). Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood, 123(1), 94–100.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Mori, M., Kaneko, N., Ueno, Y., Yamada, M., Tanaka, R., Saito, R., Shimada, I., Mori, K., & Kuromitsu, S. (2017). Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia. Investigational New Drugs, 35(5), 556–565.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Falini, B., Martelli, M. P., Bolli, N., Sportoletti, P., Liso, A., Tiacci, E., & Haferlach, T. (2011). Acute myeloid leukemia with mutated nucleophosmin (NPM1): is it a distinct entity? Blood, 117(4), 1109–1120.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Falini, B., Sportoletti, P., & Martelli, M. P. (2009). Acute myeloid leukemia with mutated NPM1: diagnosis, prognosis and therapeutic perspectives. Current Opinion in Oncology, 21(6), 573–581.PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Falini, B., et al. (2005). Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. The New England Journal of Medicine, 352(3), 254–266.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Brunetti, L., Gundry, M. C., Sorcini, D., Guzman, A. G., Huang, Y. H., Ramabadran, R., Gionfriddo, I., Mezzasoma, F., Milano, F., Nabet, B., Buckley, D. L., Kornblau, S. M., Lin, C. Y., Sportoletti, P., Martelli, M. P., Falini, B., & Goodell, M. A. (2018). Mutant NPM1 maintains the leukemic state through HOX expression. Cancer Cell, 34(3), 499–512 e9.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Brown, P., McIntyre, E., Rau, R., Meshinchi, S., Lacayo, N., Dahl, G., Alonzo, T. A., Chang, M., Arceci, R. J., & Small, D. (2007). The incidence and clinical significance of nucleophosmin mutations in childhood AML. Blood, 110(3), 979–985.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Rau, R., & Brown, P. (2009). Nucleophosmin (NPM1) mutations in adult and childhood acute myeloid leukaemia: Towards definition of a new leukaemia entity. Hematological Oncology, 27(4), 171–181.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Rau, R., Magoon, D., Greenblatt, S., Li, L., Annesley, C., Duffield, A. S., Huso, D., McIntyre, E., Clohessy, J. G., Reschke, M., Pandolfi, P. P., Small, D., & Brown, P. (2014). NPMc+ cooperates with Flt3/ITD mutations to cause acute leukemia recapitulating human disease. Experimental Hematology, 42(2), 101–113 e5.PubMedCrossRefGoogle Scholar
  139. 139.
    Kuhn, M. W., et al. (2016). Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. Cancer Discovery, 6(10), 1166–1181.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Falini, B., Brunetti, L., & Martelli, M. P. (2015). Dactinomycin in NPM1-mutated acute myeloid leukemia. The New England Journal of Medicine, 373(12), 1180–1182.PubMedCrossRefGoogle Scholar
  141. 141.
    Martelli, M. P., Gionfriddo, I., Mezzasoma, F., Milano, F., Pierangeli, S., Mulas, F., Pacini, R., Tabarrini, A., Pettirossi, V., Rossi, R., Vetro, C., Brunetti, L., Sportoletti, P., Tiacci, E., di Raimondo, F., & Falini, B. (2015). Arsenic trioxide and all-trans retinoic acid target NPM1 mutant oncoprotein levels and induce apoptosis in NPM1-mutated AML cells. Blood, 125(22), 3455–3465.PubMedCrossRefGoogle Scholar
  142. 142.
    Leroy, H., Roumier, C., Huyghe, P., Biggio, V., Fenaux, P., & Preudhomme, C. (2005). CEBPA point mutations in hematological malignancies. Leukemia, 19(3), 329–334.PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Ho, P. A., Alonzo, T. A., Gerbing, R. B., Pollard, J., Stirewalt, D. L., Hurwitz, C., Heerema, N. A., Hirsch, B., Raimondi, S. C., Lange, B., Franklin, J. L., Radich, J. P., & Meshinchi, S. (2009). Prevalence and prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia (AML): a report from the Children’s Oncology Group. Blood, 113(26), 6558–6566.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Smith, M. L., Cavenagh, J. D., Lister, T. A., & Fitzgibbon, J. (2004). Mutation of CEBPA in familial acute myeloid leukemia. The New England Journal of Medicine, 351(23), 2403–2407.PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    Pabst, T., Eyholzer, M., Haefliger, S., Schardt, J., & Mueller, B. U. (2008). Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia. Journal of Clinical Oncology, 26(31), 5088–5093.PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Yang, L., et al. (2007). A tumor suppressor and oncogene: the WT1 story. Leukemia, 21(5), 868–876.PubMedCrossRefPubMedCentralGoogle Scholar
  147. 147.
    Ho, P. A., Zeng, R., Alonzo, T. A., Gerbing, R. B., Miller, K. L., Pollard, J. A., Stirewalt, D. L., Heerema, N. A., Raimondi, S. C., Hirsch, B., Franklin, J. L., Lange, B., & Meshinchi, S. (2010). Prevalence and prognostic implications of WT1 mutations in pediatric acute myeloid leukemia (AML): a report from the Children’s Oncology Group. Blood, 116(5), 702–710.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Hollink, I. H., van den Heuvel-Eibrink, M., Zimmermann, M., Balgobind, B. V., Arentsen-Peters, S. T., Alders, M., Willasch, A., Kaspers, G. J., Trka, J., Baruchel, A., de Graaf, S. S., Creutzig, U., Pieters, R., Reinhardt, D., & Zwaan, C. M. (2009). Clinical relevance of Wilms tumor 1 gene mutations in childhood acute myeloid leukemia. Blood, 113(23), 5951–5960.PubMedCrossRefPubMedCentralGoogle Scholar
  149. 149.
    Kim, M. K., McGarry, T., O Broin, P., Flatow, J. M., Golden, A. A., & Licht, J. D. (2009). An integrated genome screen identifies the Wnt signaling pathway as a major target of WT1. Proceedings of the National Academy of Sciences of the United States of America, 106(27), 11154–11159.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Rampal, R., Alkalin, A., Madzo, J., Vasanthakumar, A., Pronier, E., Patel, J., Li, Y., Ahn, J., Abdel-Wahab, O., Shih, A., Lu, C., Ward, P. S., Tsai, J. J., Hricik, T., Tosello, V., Tallman, J. E., Zhao, X., Daniels, D., Dai, Q., Ciminio, L., Aifantis, I., He, C., Fuks, F., Tallman, M. S., Ferrando, A., Nimer, S., Paietta, E., Thompson, C. B., Licht, J. D., Mason, C. E., Godley, L. A., Melnick, A., Figueroa, M. E., & Levine, R. L. (2014). DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia. Cell Reports, 9(5), 1841–1855.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Stieglitz, E., Taylor-Weiner, A. N., Chang, T. Y., Gelston, L. C., Wang, Y. D., Mazor, T., Esquivel, E., Yu, A., Seepo, S., Olsen, S., Rosenberg, M., Archambeault, S. L., Abusin, G., Beckman, K., Brown, P. A., Briones, M., Carcamo, B., Cooper, T., Dahl, G. V., Emanuel, P. D., Fluchel, M. N., Goyal, R. K., Hayashi, R. J., Hitzler, J., Hugge, C., Liu, Y. L., Messinger, Y. H., Mahoney DH Jr, Monteleone, P., Nemecek, E. R., Roehrs, P. A., Schore, R. J., Stine, K. C., Takemoto, C. M., Toretsky, J. A., Costello, J. F., Olshen, A. B., Stewart, C., Li, Y., Ma, J., Gerbing, R. B., Alonzo, T. A., Getz, G., Gruber, T., Golub, T., Stegmaier, K., & Loh, M. L. (2015). The genomic landscape of juvenile myelomonocytic leukemia. Nature Genetics, 47(11), 1326–1333.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Holmfeldt, L., Wei, L., Diaz-Flores, E., Walsh, M., Zhang, J., Ding, L., Payne-Turner, D., Churchman, M., Andersson, A., Chen, S. C., McCastlain, K., Becksfort, J., Ma, J., Wu, G., Patel, S. N., Heatley, S. L., Phillips, L. A., Song, G., Easton, J., Parker, M., Chen, X., Rusch, M., Boggs, K., Vadodaria, B., Hedlund, E., Drenberg, C., Baker, S., Pei, D., Cheng, C., Huether, R., Lu, C., Fulton, R. S., Fulton, L. L., Tabib, Y., Dooling, D. J., Ochoa, K., Minden, M., Lewis, I. D., To, L. B., Marlton, P., Roberts, A. W., Raca, G., Stock, W., Neale, G., Drexler, H. G., Dickins, R. A., Ellison, D. W., Shurtleff, S. A., Pui, C. H., Ribeiro, R. C., Devidas, M., Carroll, A. J., Heerema, N. A., Wood, B., Borowitz, M. J., Gastier-Foster, J. M., Raimondi, S. C., Mardis, E. R., Wilson, R. K., Downing, J. R., Hunger, S. P., Loh, M. L., & Mullighan, C. G. (2013). The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nature Genetics, 45(3), 242–252.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Malinowska-Ozdowy, K., Frech, C., Schönegger, A., Eckert, C., Cazzaniga, G., Stanulla, M., zur Stadt, U., Mecklenbräuker, A., Schuster, M., Kneidinger, D., von Stackelberg, A., Locatelli, F., Schrappe, M., Horstmann, M. A., Attarbaschi, A., Bock, C., Mann, G., Haas, O. A., & Panzer-Grümayer, R. (2015). KRAS and CREBBP mutations: a relapse-linked malicious liaison in childhood high hyperdiploid acute lymphoblastic leukemia. Leukemia, 29(8), 1656–1667.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Nikolaev, S. I., et al. (2014). Frequent cases of RAS-mutated down syndrome acute lymphoblastic leukaemia lack JAK2 mutations. Nature Communications, 5, 4654.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Liu, Y., Easton, J., Shao, Y., Maciaszek, J., Wang, Z., Wilkinson, M. R., McCastlain, K., Edmonson, M., Pounds, S. B., Shi, L., Zhou, X., Ma, X., Sioson, E., Li, Y., Rusch, M., Gupta, P., Pei, D., Cheng, C., Smith, M. A., Auvil, J. G., Gerhard, D. S., Relling, M. V., Winick, N. J., Carroll, A. J., Heerema, N. A., Raetz, E., Devidas, M., Willman, C. L., Harvey, R. C., Carroll, W. L., Dunsmore, K. P., Winter, S. S., Wood, B. L., Sorrentino, B. P., Downing, J. R., Loh, M. L., Hunger, S. P., Zhang, J., & Mullighan, C. G. (2017). The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nature Genetics, 49(8), 1211–1218.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Duployez, N., Marceau-Renaut, A., Boissel, N., Petit, A., Bucci, M., Geffroy, S., Lapillonne, H., Renneville, A., Ragu, C., Figeac, M., Celli-Lebras, K., Lacombe, C., Micol, J. B., Abdel-Wahab, O., Cornillet, P., Ifrah, N., Dombret, H., Leverger, G., Jourdan, E., & Preudhomme, C. (2016). Comprehensive mutational profiling of core binding factor acute myeloid leukemia. Blood, 127(20), 2451–2459.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Faber, Z. J., Chen, X., Gedman, A. L., Boggs, K., Cheng, J., Ma, J., Radtke, I., Chao, J. R., Walsh, M. P., Song, G., Andersson, A. K., Dang, J., Dong, L., Liu, Y., Huether, R., Cai, Z., Mulder, H., Wu, G., Edmonson, M., Rusch, M., Qu, C., Li, Y., Vadodaria, B., Wang, J., Hedlund, E., Cao, X., Yergeau, D., Nakitandwe, J., Pounds, S. B., Shurtleff, S., Fulton, R. S., Fulton, L. L., Easton, J., Parganas, E., Pui, C. H., Rubnitz, J. E., Ding, L., Mardis, E. R., Wilson, R. K., Gruber, T. A., Mullighan, C. G., Schlenk, R. F., Paschka, P., Döhner, K., Döhner, H., Bullinger, L., Zhang, J., Klco, J. M., & Downing, J. R. (2016). The genomic landscape of core-binding factor acute myeloid leukemias. Nature Genetics, 48(12), 1551–1556.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Pollard, J. A., Alonzo, T. A., Gerbing, R. B., Ho, P. A., Zeng, R., Ravindranath, Y., Dahl, G., Lacayo, N. J., Becton, D., Chang, M., Weinstein, H. J., Hirsch, B., Raimondi, S. C., Heerema, N. A., Woods, W. G., Lange, B. J., Hurwitz, C., Arceci, R. J., Radich, J. P., Bernstein, I. D., Heinrich, M. C., & Meshinchi, S. (2010). Prevalence and prognostic significance of KIT mutations in pediatric patients with core binding factor AML enrolled on serial pediatric cooperative trials for de novo AML. Blood, 115(12), 2372–2379.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Shimada, A., Taki, T., Tabuchi, K., Tawa, A., Horibe, K., Tsuchida, M., Hanada, R., Tsukimoto, I., & Hayashi, Y. (2006). KIT mutations, and not FLT3 internal tandem duplication, are strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21): a study of the Japanese Childhood AML Cooperative Study Group. Blood, 107(5), 1806–1809.PubMedCrossRefGoogle Scholar
  160. 160.
    Ostrem, J. M., & Shokat, K. M. (2016). Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nature Reviews. Drug Discovery, 15(11), 771–785.PubMedCrossRefGoogle Scholar
  161. 161.
    Welsch, M. E., Kaplan, A., Chambers, J. M., Stokes, M. E., Bos, P. H., Zask, A., Zhang, Y., Sanchez-Martin, M., Badgley, M. A., Huang, C. S., Tran, T. H., Akkiraju, H., Brown, L. M., Nandakumar, R., Cremers, S., Yang, W. S., Tong, L., Olive, K. P., Ferrando, A., & Stockwell, B. R. (2017). Multivalent small-molecule Pan-RAS inhibitors. Cell, 168(5), 878–889 e29.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Schittenhelm, M. M., Shiraga, S., Schroeder, A., Corbin, A. S., Griffith, D., Lee, F. Y., Bokemeyer, C., Deininger, M. W., Druker, B. J., & Heinrich, M. C. (2006). Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Research, 66(1), 473–481.PubMedCrossRefGoogle Scholar
  163. 163.
    Yang, L., Rau, R., & Goodell, M. A. (2015). DNMT3A in haematological malignancies. Nature Reviews. Cancer, 15(3), 152–165.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Bowman, R. L., & Levine, R. L. (2017). TET2 in Normal and Malignant Hematopoiesis. Cold Spring Harbor Perspectives in Medicine, 7(8).Google Scholar
  165. 165.
    Shih, A. H., & Levine, R. L. (2012). IDH1 mutations disrupt blood, brain, and barriers. Cancer Cell, 22(3), 285–287.PubMedCrossRefGoogle Scholar
  166. 166.
    Ho, P. A., et al. (2011). Leukemic mutations in the methylation-associated genes DNMT3A and IDH2 are rare events in pediatric AML: a report from the Children’s Oncology Group. Pediatric Blood & Cancer, 57(2), 204–209.CrossRefGoogle Scholar
  167. 167.
    Busque, L., Buscarlet, M., Mollica, L., & Levine, R. L. (2018). Concise review: age-related clonal hematopoiesis: stem cells tempting the devil. Stem Cells, 36(9), 1287–1294.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Golub, D., et al. (2019). Mutant isocitrate dehydrogenase inhibitors as targeted cancer therapeutics. Frontiers in Oncology, 9, 417.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Shih, A. H., Abdel-Wahab, O., Patel, J. P., & Levine, R. L. (2012). The role of mutations in epigenetic regulators in myeloid malignancies. Nature Reviews. Cancer, 12(9), 599–612.PubMedCrossRefGoogle Scholar
  170. 170.
    Buchanan, J., & Tirado, C. A. (2016). A t(16;21)(p11;q22) in acute myeloid leukemia (AML) resulting in fusion of the FUS/TLS and ERG genes: a review of the literature. J Assoc Genet Technol, 42(1), 24–33.PubMedGoogle Scholar
  171. 171.
    Borel, C., Dastugue, N., Cances-Lauwers, V., Mozziconacci, M. J., Prebet, T., Vey, N., Pigneux, A., Lippert, E., Visanica, S., Legrand, F., Rault, J. P., Taviaux, S., Bastard, C., Mugneret, F., Collonges Rames, M. A., Gachard, N., Talmant, P., Delabesse, E., & Récher, C. (2012). PICALM-MLLT10 acute myeloid leukemia: a French cohort of 18 patients. Leukemia Research, 36(11), 1365–1369.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Division of Pediatric Hematology/OncologyTexas Children’s Cancer Center, Baylor College of MedicineHoustonUSA

Personalised recommendations