Skip to main content

Advertisement

SpringerLink
Log in

Chronic Myeloid Leukemia: Beyond BCR-ABL1

  • Molecular Testing and Diagnostics (J Khoury, Section Editor)
  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

Purpose of review

In this review, we emphasize up-to-date practical cytogenetic and molecular aspects of chronic myeloid leukemia (CML) and summarize current knowledge on tyrosine kinase inhibitor (TKI) resistance and treatment response monitoring of CML.

Recent findings

The introduction of TKIs has changed the natural course of CML and markedly improved patient survival. Over the past decades, many research efforts were devoted to elucidating the leukemogenic mechanisms of BCR-ABL1 and developing novel TKIs. More recent studies have attempted to answer new questions that have emerged in the TKI era, such as the cytogenetic and molecular bases of treatment failure and disease progression, the clinical impact of genetic aberrations in Philadelphia chromosome (Ph)-positive and Ph-negative cells, and the biological significance of Ph secondarily acquired during therapy of other hematological neoplasms.

Summary

Recent progresses in the understanding of the cytogenetic and molecular mechanisms underlying therapeutic failure and disease progression have improved the risk stratification of CML and will be helpful in the design of novel therapeutic strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer. 2005;5(3):172–83.

    CAS  PubMed  Google Scholar 

  2. Ahmed W, Van Etten RA. Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: tyrosine-kinase inhibitor combinations and beyond. Hematology Am Soc Hematol Educ Program. 2013;2013:189–200.

    PubMed  PubMed Central  Google Scholar 

  3. Cilloni D, Saglio G. Molecular pathways: BCR-ABL. Clin Cancer Res. 2012;18(4):930–7.

    CAS  PubMed  Google Scholar 

  4. Goh HG, Hwang JY, Kim SH, Lee YH, Kim YL, Kim DW. Comprehensive analysis of BCR-ABL transcript types in Korean CML patients using a newly developed multiplex RT-PCR. Transl Res. 2006;148(5):249–56.

    CAS  PubMed  Google Scholar 

  5. Arun AK, Senthamizhselvi A, Mani S, Vinodhini K, Janet NB, Lakshmi KM, et al. Frequency of rare BCR-ABL1 fusion transcripts in chronic myeloid leukemia patients. Int J Lab Hematol. 2017;39(3):235–42.

    CAS  PubMed  Google Scholar 

  6. Melo JV, Barnes DJ. Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer. 2007;7(6):441–53.

    CAS  PubMed  Google Scholar 

  7. Gong Z, Medeiros LJ, Cortes JE, Zheng L, Khoury JD, Wang W, et al. Clinical and prognostic significance of e1a2 BCR-ABL1 transcript subtype in chronic myeloid leukemia. Blood Cancer J. 2017;7(7):e583.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Li S, Ilaria RL Jr, Million RP, Daley GQ, van Etten R. The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity. J Exp Med. 1999;189(9):1399–412.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Castor A, Nilsson L, Åstrand-Grundström I, Buitenhuis M, Ramirez C, Anderson K, et al. Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia. Nat Med. 2005;11(6):630–7.

    CAS  PubMed  Google Scholar 

  10. Lugo TG, Witte ON. The BCR-ABL oncogene transforms Rat-1 cells and cooperates with v-myc. Mol Cell Biol. 1989;9(3):1263–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kelliher M, Knott A, McLaughlin J, Witte ON, Rosenberg N. Differences in oncogenic potency but not target cell specificity distinguish the two forms of the BCR/ABL oncogene. Mol Cell Biol. 1991;11(9):4710–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Voncken JW, Kaartinen V, Pattengale PK, Germeraad WT, Groffen J, Heisterkamp N. BCR/ABL P210 and P190 cause distinct leukemia in transgenic mice. Blood. 1995;86(12):4603–11.

    CAS  PubMed  Google Scholar 

  13. Reckel S, Hamelin R, Georgeon S, Armand F, Jolliet Q, Chiappe D, et al. Differential signaling networks of Bcr-Abl p210 and p190 kinases in leukemia cells defined by functional proteomics. Leukemia. 2017;31(7):1502–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Danial NN, Pernis A, Rothman PB. Jak-STAT signaling induced by the v-abl oncogene. Science. 1995;269(5232):1875–7.

    CAS  PubMed  Google Scholar 

  15. Ilaria RL Jr, van Etten RA. P210 and P190BCR/ABL induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. J Biol Chem. 1996;271(49):31704–10.

    CAS  PubMed  Google Scholar 

  16. Kaplan MH, Schindler U, Smiley ST, Grusby MJ. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity. 1996;4(3):313–9.

    CAS  PubMed  Google Scholar 

  17. Telegeev GD, Dubrovska AN, Nadgorna VA, Dybkov MV, Zavelevich MP, Maliuta SS, et al. Immunocytochemical study of Bcr and Bcr-Abl localization in K562 cells. Exp Oncol. 2010;32(2):81–3.

    CAS  PubMed  Google Scholar 

  18. Heisterkamp N, Voncken JW, Senadheera D, Gonzalez-Gomez I, Reichert A, Haataja L, et al. Reduced oncogenicity of p190 Bcr/Abl F-actin-binding domain mutants. Blood. 2000;96(6):2226–32.

    CAS  PubMed  Google Scholar 

  19. Hantschel O, Wiesner S, Güttler T, Mackereth CD, Rix LL, Mikes Z, et al. Structural basis for the cytoskeletal association of Bcr-Abl/c-Abl. Mol Cell. 2005;19(4):461–73.

    CAS  PubMed  Google Scholar 

  20. Wee P, Wang Z. Epidermal growth factor receptor cell proliferation signaling pathways. Cancers (Basel). 2017;9(5):52.

  21. Birge RB, et al. Crk and CrkL adaptor proteins: networks for physiological and pathological signaling. Cell Commun Signal. 2009;7:13.

    PubMed  PubMed Central  Google Scholar 

  22. Varticovski L, Daley GQ, Jackson P, Baltimore D, Cantley LC. Activation of phosphatidylinositol 3-kinase in cells expressing abl oncogene variants. Mol Cell Biol. 1991;11(2):1107–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Jain SK, Susa M, Keeler ML, Carlesso N, Druker B, Varticovski L. PI 3-kinase activation in BCR/abl-transformed hematopoietic cells does not require interaction of p85 SH2 domains with p210 BCR/abl. Blood. 1996;88(5):1542–50.

    CAS  PubMed  Google Scholar 

  24. Shuai K, Halpern J, ten Hoeve J, Rao X, Sawyers CL. Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia. Oncogene. 1996;13(2):247–54.

    CAS  PubMed  Google Scholar 

  25. Gaymes TJ, Mufti GJ, Rassool FV. Myeloid leukemias have increased activity of the nonhomologous end-joining pathway and concomitant DNA misrepair that is dependent on the Ku70/86 heterodimer. Cancer Res. 2002;62(10):2791–7.

    CAS  PubMed  Google Scholar 

  26. Hoover RR, Gerlach MJ, Koh EY, Daley GQ. Cooperative and redundant effects of STAT5 and Ras signaling in BCR/ABL transformed hematopoietic cells. Oncogene. 2001;20(41):5826–35.

    CAS  PubMed  Google Scholar 

  27. Nowicki MO, Falinski R, Koptyra M, Slupianek A, Stoklosa T, Gloc E, et al. BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen species-dependent DNA double-strand breaks. Blood. 2004;104(12):3746–53.

    CAS  PubMed  Google Scholar 

  28. Albajar M, Gomez-Casares MT, Llorca J, Mauleon I, Vaque JP, Acosta JC, et al. MYC in chronic myeloid leukemia: induction of aberrant DNA synthesis and association with poor response to imatinib. Mol Cancer Res. 2011;9(5):564–76.

    CAS  PubMed  Google Scholar 

  29. •• Johansson B, Fioretos T, Mitelman F. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol. 2002;107(2):76–94 Comprehensive and elegant review of cytogenetic changes in CML in pre-TKI era.

    CAS  PubMed  Google Scholar 

  30. Mu Q, Ma Q, Wang Y, Chen Z, Tong X, Chen FF, et al. Cytogenetic profile of 1,863 Ph/BCR-ABL-positive chronic myelogenous leukemia patients from the Chinese population. Ann Hematol. 2012;91(7):1065–72.

    PubMed  Google Scholar 

  31. Calabretta B, Perrotti D. The biology of CML blast crisis. Blood. 2004;103(11):4010–22.

    CAS  PubMed  Google Scholar 

  32. •• Baccarani M, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872–84 Updated recommendations for treatment and monitoring of CML.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Fioretos T. Chronic myeloid leukemia. In: Heim S, Mitelman F, editors. Cancer cytogenetics. Hoboken: Wiley; 2016. p. 153–74.

    Google Scholar 

  34. Soverini S, Branford S, Nicolini FE, Talpaz M, Deininger MW, Martinelli G, et al. Implications of BCR-ABL1 kinase domain-mediated resistance in chronic myeloid leukemia. Leuk Res. 2014;38(1):10–20.

    CAS  PubMed  Google Scholar 

  35. Hanfstein B, Muller MC, Hochhaus A. Response-related predictors of survival in CML. Ann Hematol. 2015;94(Suppl 2):S227–39.

    PubMed  Google Scholar 

  36. Hehlmann R, Hasford J, Pfirrmann M, Lauseker M, Saußele S, Hochhaus A, et al. Reply to H. Kantarjian et al. J Clin Oncol. 2014;32(27):3078–9.

    PubMed  Google Scholar 

  37. Chen Z, Medeiros LJ, Kantajian HM, Zheng L, Gong Z, Patel KP, et al. Differential depth of treatment response required for optimal outcome in patients with blast phase versus chronic phase of chronic myeloid leukemia. Blood Cancer J. 2017;7(2):e521.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Chaitanya PK, Kumar KA, Stalin B, Sadashivudu G, Srinivas ML. The role of mutation testing in patients with chronic myeloid leukemia in chronic phase after imatinib failure and their outcomes after treatment modification: single-institutional experience over 13 years. Indian J Med Paediatr Oncol. 2017;38(3):328–33.

    PubMed  PubMed Central  Google Scholar 

  39. Quintas-Cardama A, Kantarjian HM, Cortes JE. Mechanisms of primary and secondary resistance to imatinib in chronic myeloid leukemia. Cancer Control. 2009;16(2):122–31.

    PubMed  Google Scholar 

  40. Jabbour E, Kantarjian H, Jones D, Talpaz M, Bekele N, O'Brien S, et al. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia. 2006;20(10):1767–73.

    CAS  PubMed  Google Scholar 

  41. Soverini S, Colarossi S, Gnani A, Rosti G, Castagnetti F, Poerio A, et al. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res. 2006;12(24):7374–9.

    CAS  PubMed  Google Scholar 

  42. O'Hare T, Zabriskie MS, Eiring AM, Deininger MW. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat Rev Cancer. 2012;12(8):513–26.

    CAS  PubMed  Google Scholar 

  43. Apperley JF. Part I: Mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol. 2007;8(11):1018–29.

    CAS  PubMed  Google Scholar 

  44. Sherbenou DW, Hantschel O, Kaupe I, Willis S, Bumm T, Turaga LP, et al. BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib. Blood. 2010;116(17):3278–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Barnes DJ, Palaiologou D, Panousopoulou E, Schultheis B, Yong ASM, Wong A, et al. Bcr-Abl expression levels determine the rate of development of resistance to imatinib mesylate in chronic myeloid leukemia. Cancer Res. 2005;65(19):8912–9.

    CAS  PubMed  Google Scholar 

  46. Jiang X, Zhao Y, Smith C, Gasparetto M, Turhan A, Eaves A, et al. Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. Leukemia. 2007;21(5):926–35.

    CAS  PubMed  Google Scholar 

  47. Thomas J, Wang L, Clark RE, Pirmohamed M. Active transport of imatinib into and out of cells: implications for drug resistance. Blood. 2004;104(12):3739–45.

    CAS  PubMed  Google Scholar 

  48. Hamilton A, Helgason GV, Schemionek M, Zhang B, Myssina S, Allan EK, et al. Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood. 2012;119(6):1501–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Perl A, Carroll M. BCR-ABL kinase is dead; long live the CML stem cell. J Clin Invest. 2011;121(1):22–5.

    CAS  PubMed  Google Scholar 

  50. Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest. 2011;121(1):396–409.

    CAS  PubMed  Google Scholar 

  51. Wang W, Cortes JE, Lin P, Beaty MW, Ai D, Amin HM, et al. Clinical and prognostic significance of 3q26.2 and other chromosome 3 abnormalities in CML in the era of tyrosine kinase inhibitors. Blood. 2015;126(14):1699–706.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. •• Chen Z, et al. Cytogenetic landscape and impact in blast phase of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy. Leukemia. 2017;31(3):585–92 Demonstration of changes in ACA landscape, prognostic impact of ACAs, and relationship between ACAs in CML-BP in TKI era.

    CAS  PubMed  Google Scholar 

  53. Wu J, Meng F, Kong LY, Peng Z, Ying Y, Bornmann WG, et al. Association between imatinib-resistant BCR-ABL mutation-negative leukemia and persistent activation of LYN kinase. J Natl Cancer Inst. 2008;100(13):926–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Quentmeier H, Eberth S, Romani J, Zaborski M, Drexler HG. BCR-ABL1-independent PI3Kinase activation causing imatinib-resistance. J Hematol Oncol. 2011;4:6.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011;117(8):e75–87.

    CAS  PubMed  Google Scholar 

  56. White DL, Saunders VA, Dang P, Engler J, Venables A, Zrim S, et al. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood. 2007;110(12):4064–72.

    CAS  PubMed  Google Scholar 

  57. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th ed. Switzerland: WHO Press; 2017.

    Google Scholar 

  58. • Wang W, et al. Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy. Blood. 2016;127(22):2742–50 Stratification of CML patients based on ACA-associated patient survival in TKI era.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. •• Gong Z, et al. Cytogenetics-based risk prediction of blastic transformation of chronic myeloid leukemia in the era of TKI therapy. Blood Adv. 2017;1(26):2541–52 Four-tier stratification of CML based on ACA-associated risk of blastic transformation.

    PubMed  PubMed Central  Google Scholar 

  60. Johansson B, Fioretos T, Billström R, Mitelman F. Aberrant cytogenetic evolution pattern of Philadelphia-positive chronic myeloid leukemia treated with interferon-alpha. Leukemia. 1996;10(7):1134–8.

    CAS  PubMed  Google Scholar 

  61. Mitelman F, Johansson B, Mertens F. https://cgap.nci.nih.gov/Chromosomes/Mitelman. 2001. Accessed 1 Aug 2018.

  62. Gaiger A, Henn T, Hörth E, Geissler K, Mitterbauer G, Maier-Dobersberger T, et al. Increase of BCR-ABL chimeric mRNA expression in tumor cells of patients with chronic myeloid leukemia precedes disease progression. Blood. 1995;86(6):2371–8.

    CAS  PubMed  Google Scholar 

  63. Guo JQ, Wang JY, Arlinghaus RB. Detection of BCR-ABL proteins in blood cells of benign phase chronic myelogenous leukemia patients. Cancer Res. 1991;51(11):3048–51.

    CAS  PubMed  Google Scholar 

  64. Barnes DJ, Schultheis B, Adedeji S, Melo JV. Dose-dependent effects of Bcr-Abl in cell line models of different stages of chronic myeloid leukemia. Oncogene. 2005;24(42):6432–40.

    CAS  PubMed  Google Scholar 

  65. Cambier N, Chopra R, Strasser A, Metcalf D, Elefanty AG. BCR-ABL activates pathways mediating cytokine independence and protection against apoptosis in murine hematopoietic cells in a dose-dependent manner. Oncogene. 1998;16(3):335–48.

    CAS  PubMed  Google Scholar 

  66. Grossmann V, Kohlmann A, Zenger M, Schindela S, Eder C, Weissmann S, et al. A deep-sequencing study of chronic myeloid leukemia patients in blast crisis (BC-CML) detects mutations in 76.9% of cases. Leukemia. 2011;25(3):557–60.

    CAS  PubMed  Google Scholar 

  67. Notari M, Neviani P, Santhanam R, Blaser BW, Chang JS, Galietta A, et al. A MAPK/HNRPK pathway controls BCR/ABL oncogenic potential by regulating MYC mRNA translation. Blood. 2006;107(6):2507–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Jennings BA, Mills KI. c-myc locus amplification and the acquisition of trisomy 8 in the evolution of chronic myeloid leukaemia. Leuk Res. 1998;22(10):899–903.

    CAS  PubMed  Google Scholar 

  69. Jamieson CH, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004;351(7):657–67.

    CAS  PubMed  Google Scholar 

  70. Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A. 2006;103(8):2794–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Zhang SJ, Ma LY, Huang QH, Li G, Gu BW, Gao XD, et al. Gain-of-function mutation of GATA-2 in acute myeloid transformation of chronic myeloid leukemia. Proc Natl Acad Sci U S A. 2008;105(6):2076–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Hehlmann R. How I treat CML blast crisis. Blood. 2012;120(4):737–47.

    CAS  PubMed  Google Scholar 

  73. Sill H, Goldman JM, Cross NC. Homozygous deletions of the p16 tumor-suppressor gene are associated with lymphoid transformation of chronic myeloid leukemia. Blood. 1995;85(8):2013–6.

    CAS  PubMed  Google Scholar 

  74. Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453(7191):110–4.

    CAS  PubMed  Google Scholar 

  75. Yin Y, Li J, Yan W, Cheng Z, Sun N, Zhang G. CEBPA mutation in a case of chronic myeloid leukemia presenting in myeloid blast crisis. Leuk Lymphoma. 2017;58(3):708–10.

    PubMed  Google Scholar 

  76. Dash AB, Williams IR, Kutok JL, Tomasson MH, Anastasiadou E, Lindahl K, et al. A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9. Proc Natl Acad Sci U S A. 2002;99(11):7622–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Nucifora G, Birn DJ, Espinosa R 3rd, Erickson P, LeBeau M, Roulston D, et al. Involvement of the AML1 gene in the t(3;21) in therapy-related leukemia and in chronic myeloid leukemia in blast crisis. Blood. 1993;81(10):2728–34.

    CAS  PubMed  Google Scholar 

  78. Di Giacomo D, et al. Blast crisis Ph+ chronic myeloid leukemia with NUP98/HOXA13 up-regulating MSI2. Mol Cytogenet. 2014;7:42.

    PubMed  PubMed Central  Google Scholar 

  79. Shteper PJ, Ben-Yehuda D. Molecular evolution of chronic myeloid leukaemia. Semin Cancer Biol. 2001;11(4):313–23.

    CAS  PubMed  Google Scholar 

  80. Heller G, Topakian T, Altenberger C, Cerny-Reiterer S, Herndlhofer S, Ziegler B, et al. Next-generation sequencing identifies major DNA methylation changes during progression of Ph+ chronic myeloid leukemia. Leukemia. 2016;30(9):1861–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Jelinek J, Gharibyan V, Estecio MRH, Kondo K, He R, Chung W, et al. Aberrant DNA methylation is associated with disease progression, resistance to imatinib and shortened survival in chronic myelogenous leukemia. PLoS One. 2011;6(7):e22110.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Issa JP, Kantarjian H, Mohan A, O'Brien S, Cortes J, Pierce S, et al. Methylation of the ABL1 promoter in chronic myelogenous leukemia: lack of prognostic significance. Blood. 1999;93(6):2075–80.

    CAS  PubMed  Google Scholar 

  83. Kim T, Tyndel MS, Kim HJ, Ahn JS, Choi SH, Park HJ, et al. Spectrum of somatic mutation dynamics in chronic myeloid leukemia following tyrosine kinase inhibitor therapy. Blood. 2017;129(1):38–47.

    CAS  PubMed  Google Scholar 

  84. Terre C, et al. Report of 34 patients with clonal chromosomal abnormalities in Philadelphia-negative cells during imatinib treatment of Philadelphia-positive chronic myeloid leukemia. Leukemia. 2004;18(8):1340–6.

    CAS  PubMed  Google Scholar 

  85. O'Dwyer ME, Gatter KM, Loriaux M, Druker BJ, Olson SB, Magenis RE, et al. Demonstration of Philadelphia chromosome negative abnormal clones in patients with chronic myelogenous leukemia during major cytogenetic responses induced by imatinib mesylate. Leukemia. 2003;17(3):481–7.

    CAS  PubMed  Google Scholar 

  86. Jabbour E, Kantarjian HM, Abruzzo LV, O'Brien S, Garcia-Manero G, Verstovsek S, et al. Chromosomal abnormalities in Philadelphia chromosome negative metaphases appearing during imatinib mesylate therapy in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood. 2007;110(8):2991–5.

    CAS  PubMed  Google Scholar 

  87. Medina J, Kantarjian H, Talpaz M, O'Brien S, Garcia-Manero G, Giles F, et al. Chromosomal abnormalities in Philadelphia chromosome-negative metaphases appearing during imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. Cancer. 2003;98(9):1905–11.

    CAS  PubMed  Google Scholar 

  88. Deininger MW, Cortes J, Paquette R, Park B, Hochhaus A, Baccarani M, et al. The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in Philadelphia chromosome-negative cells. Cancer. 2007;110(7):1509–19.

    PubMed  Google Scholar 

  89. Kovitz C, Kantarjian H, Garcia-Manero G, Abruzzo LV, Cortes J. Myelodysplastic syndromes and acute leukemia developing after imatinib mesylate therapy for chronic myeloid leukemia. Blood. 2006;108(8):2811–3.

    CAS  PubMed  Google Scholar 

  90. Groves MJ, Sales M, Baker L, Griffiths M, Pratt N, Tauro S. Factors influencing a second myeloid malignancy in patients with Philadelphia-negative −7 or del(7q) clones during tyrosine kinase inhibitor therapy for chronic myeloid leukemia. Cancer Genet. 2011;204(1):39–44.

    CAS  PubMed  Google Scholar 

  91. • Kurt H, Zheng L, Kantarjian HM, Tang G, Ravandi-Kashani F, Garcia-Manero G, et al. Secondary Philadelphia chromosome acquired during therapy of acute leukemia and myelodysplastic syndrome. Mod Pathol. 2018. Comprehensive study of emergence of secondary Ph and its significance.;31:1141–54.

    CAS  PubMed  Google Scholar 

  92. Chen Z, Wang W, Verstovsek S, Cortes JE, Medeiros LJ, Hu S. Chronic myelogenous leukemia in patients with MPL or JAK2 mutation-positive myeloproliferative neoplasm. Int J Lab Hematol. 2015;37(6):e150–2.

    CAS  PubMed  Google Scholar 

  93. Soderquist CR, Ewalt MD, Czuchlewski DR, Geyer JT, Rogers HJ, Hsi ED, et al. Myeloproliferative neoplasms with concurrent BCR-ABL1 translocation and JAK2 V617F mutation: a multi-institutional study from the bone marrow pathology group. Mod Pathol. 2018;31(5):690–704.

    CAS  PubMed  Google Scholar 

  94. Pingali SR, et al. Emergence of chronic myelogenous leukemia from a background of myeloproliferative disorder: JAK2V617F as a potential risk factor for BCR-ABL translocation. Clin Lymphoma Myeloma. 2009;9(5):E25–9.

    PubMed  Google Scholar 

  95. Mirza I, Frantz C, Clarke G, Voth AJ, Turner R. Transformation of polycythemia vera to chronic myelogenous leukemia. Arch Pathol Lab Med. 2007;131(11):1719–24.

    CAS  PubMed  Google Scholar 

  96. Shimizu H, Yokohama A, Hatsumi N, Takada S, Handa H, Sakura T, et al. Philadelphia chromosome-positive mixed phenotype acute leukemia in the imatinib era. Eur J Haematol. 2014;93(4):297–301.

    CAS  PubMed  Google Scholar 

  97. de Franca Azevedo I, et al. Frequency of p190 and p210 BCR-ABL rearrangements and survival in Brazilian adult patients with acute lymphoblastic leukemia. Rev Bras Hematol Hemoter. 2014;36(5):351–5.

    PubMed  PubMed Central  Google Scholar 

  98. Jaso J, Thomas DA, Cunningham K, Jorgensen JL, Kantarjian HM, Medeiros LJ, et al. Prognostic significance of immunophenotypic and karyotypic features of Philadelphia positive B-lymphoblastic leukemia in the era of tyrosine kinase inhibitors. Cancer. 2011;117(17):4009–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Verrma SP, Dutta TK, Vinod KV, Dubashi B, Ariga KK. Philadelphia chromosome positive pre-T cell acute lymphoblastic leukemia: a rare case report and short review. Indian J Hematol Blood Transfus. 2014;30(Suppl 1):177–9.

    PubMed  PubMed Central  Google Scholar 

  100. Soupir CP, Vergilio JA, Cin PD, Muzikansky A, Kantarjian H, Jones D, et al. Philadelphia chromosome-positive acute myeloid leukemia: a rare aggressive leukemia with clinicopathologic features distinct from chronic myeloid leukemia in myeloid blast crisis. Am J Clin Pathol. 2007;127(4):642–50.

    PubMed  Google Scholar 

  101. Konopleva M, et al. Molecular biology and cytogenetics of chronic myeloid leukemia. In: P.H. Wiemik, J.P. Dutcher, and M.A. Gertz, eds. Neoplastic Disease of the Blood. Springer. 2018:29-47.

  102. Reboursiere E, Chantepie S, Gac AC, Reman O. Rare but authentic Philadelphia-positive acute myeloblastic leukemia: two case reports and a literature review of characteristics, treatment and outcome. Hematol Oncol Stem Cell Ther. 2015;8(1):28–33.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology & Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA

    Ting Zhou

  2. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0072, Houston, TX, 77030, USA

    L. Jeffrey Medeiros & Shimin Hu

Authors
  1. Ting Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. Jeffrey Medeiros
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shimin Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ting Zhou or Shimin Hu.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Molecular Testing and Diagnostics

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, T., Medeiros, L.J. & Hu, S. Chronic Myeloid Leukemia: Beyond BCR-ABL1. Curr Hematol Malig Rep 13, 435–445 (2018). https://doi.org/10.1007/s11899-018-0474-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-018-0474-6

Keywords

Search

Navigation