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Precision Molecular Pathology of Myeloid Neoplasms pp 311–341Cite as

Myeloid and Lymphoid Neoplasms with Eosinophilia and Abnormalities of PDGFRA, PDGFRB, FGFR1, or t(8;9)(p22;p24.1);PCM1-JAK2

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Part of the book series: Molecular Pathology Library ((MPLB,volume 12))

Abstract

Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1 were first recognized by the WHO in the 2008 edition. In the 2016 WHO, myeloid and lymphoid neoplasms with eosinophilia and t(8;9)(p22;p24.1);PCM1-JAK2 will be recognized as a provisional entity. These neoplasms more commonly affect men and occur in a broad age range, but with a median age of forties to fifties. They represent a heterogeneous group of neoplasms in which eosinophilia is typical but not required. Patients with abnormalities of PDGFRA usually present with features of chronic eosinophilic leukemia. Patients with abnormalities of PDGFRB often present with features of chronic myelomonocytic leukemia with eosinophilia, whereas patients with abnormalities of FGFR1 or t(8;9)(p22;p24.1); PCM1-JAK2 can have a more heterogeneous presentation. Conventional karyotyping can detect most of the aforementioned abnormalities; however, abnormalities of PDGFRA are often the result of a cryptic 4q12 deletion, requiring FISH analysis. Given the relative rarity of these neoplasms, PCR analysis is not available at routine laboratories, but has been proven successful in monitoring molecular disease in patients with known fusion partners. The recognition of these neoplasms is vital as patients with abnormalities of PDGFRA and PDGFRB are exquisitely sensitive to imatinib. Furthermore, JAK2 inhibitors are likely to play a substantial role in patients with t(8;9)(p22;p24.1); PCM1-JAK2. Unfortunately, effective targeted therapy has not been discovered for patients with abnormalities of FGFR1 to date. This chapter will further divulge additional details regarding this heterogeneous group of neoplasms including description of various fusion partners with PDGFRA, PDGFRB, and FGFR1.

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References

  1. Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, Kutok J, Clark J, Galinsky I, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1.Genes as a therapeutic target of imatinib in idiopathic Hypereosinophilic syndrome. N Engl J Med. 2003;348(13):1201–14.

    Article  CAS  PubMed  Google Scholar 

  2. Bain BJ, Gilliland DG, Vardiman JW, Horny HP. Chronic eosinophilic leukemia, not otherwise specified. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. World Health Organization classification of Tumours. Pathology and Genetics or Tumours of Haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. p. 51–3.

    Google Scholar 

  3. Gotlib J. World Health Organization-defined eosinophilic disorders: 2015 update on diagnosis, risk stratification, and management. Am J Hematol. 2015;90(11):1078–89.

    Article  CAS  Google Scholar 

  4. Bain BJ, Gilliland DG, Horny HP, Vardiman JW. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. World Health Organization classification of tumours. Pathology and genetics or tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. p. 68–73.

    Google Scholar 

  5. Klion AD, Noel P, Akin C, Law MA, Gilliland DG, Cools J, et al. Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness. Blood. 2003;101(12):4660–6.

    Article  CAS  PubMed  Google Scholar 

  6. Trempat P, Villalva C, Laurent G, Armstrong F, Delsol G, Dastugue N, et al. Chronic myeloproliferative disorders with rearrangement of the platelet-derived growth factor α receptor: a new clinical target for STI571/Glivec. Oncogene. 2003;22(36):5702–6.

    Article  CAS  PubMed  Google Scholar 

  7. Savage NM, George TI, Gotlib J. Myeloid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, and FGFR1: a review. Int Jnl Lab Hem. 2013;35:491–500.

    Article  CAS  Google Scholar 

  8. Metzgeroth G, Walz C, Score J, Siebert R, Schnittger S, Haferlach C, et al. Recurrent finding of the FIP1L1-PDGFRA fusion gene in eosinophilia-associated acute myeloid leukemia and lymphoblastic T-cell lymphoma. Leukemia. 2007;21(6):1183–8.

    Article  CAS  PubMed  Google Scholar 

  9. Chen D, Bachanova V, Ketterling RP, Begna KH, Hanson CA, Viswanatha DS. A case of nonleukemia myeloid sarcoma with FIP1L1-PDGFRA rearrangement: an unusual presentation of a rare disease. Am J Surg Pathol. 2013;37(1):147–51.

    Article  PubMed  Google Scholar 

  10. Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 2008;22(10):1276–312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yoo C, Ryu MH, Jo J, Park I, Ryoo BY, Kang YK. Efficacy of Imatinib in Patients with Platelet-Derived Growth Factor Receptor Alpha–Mutated Gastrointestinal Stromal Tumors. Cancer Res Treat. 2016;48(2):546–52.

    Article  CAS  PubMed  Google Scholar 

  12. Ozawa T, Brennan CW, Wang L, Squatrito M, Sasayama T, Nakada M, et al. PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas. Genes Dev. 2010;24(19):2205–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Huss S, Wardelmann E, Goltz D, Binot E, Hartmann W, Merkelbach-Bruse S, et al. Activating PDGFRA mutations in inflammatory fibroid polyps occur in exons 12, 14, and 18 and are associated with tumor localization. Histopathology. 2012;61(1):59–68.

    Article  PubMed  Google Scholar 

  15. Holtkamp N, Okuducu AF, Mucha J, Afanasieva A, Hartmann C, Atallah I, et al. Mutation and expression of PDGFRA and KIT in malignant peripheral nerve sheath tumors, and its implications for imatinib sensitivity. Carcinogenesis. 2006;27(3):664–71.

    Article  CAS  PubMed  Google Scholar 

  16. Kaufmann I, Martin G, Friedlein A, Langen H, Keller W. Human Fip1 is a subunit of CPSF that binds to U-rich RNA elements and stimulates poly(A) polymerase. EMBO J. 2004;23(3):616–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pardanani A, Ketterling RP, Brockman SR, Flynn HC, Paternoster SF, Shearer BM, et al. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood. 2003;102(9):3093–6.

    Article  CAS  PubMed  Google Scholar 

  18. Baxter EJ, Hochhaus A, Bolufer P, Reiter A, Fernandez JM, Senent L, et al. The t(4;22)(9q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA. Hum Mol Genet. 2002;11(12):1391–7.

    Article  CAS  PubMed  Google Scholar 

  19. Tashiro H, Shirasaki R, Noguchi M, Gotoh M, Kawasugi K, Shirafuji N. Molecular analysis of chronic eosinophilic leukemia with t(4;10) showing good response to imatinib mesylate. Int Jnl Hem. 2006;83(5):433–8.

    Article  CAS  Google Scholar 

  20. Stover EH, Chen J, Folens C, Lee BH, Mentens N, Marynen P, et al. Activation of FIP1L1-PDGFRα requires disruption of the juxtamembrane domain of PDGFRα and is FIP1L1 independent. Proc Natl Acad Sci U S A. 2006;103(21):8078–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Capovilla M, Cayuela JM, Bilhou-Nabera C, Gardin C, Letestu R, Baran-Marzak F, et al. Synchronous FIP1L1-PDGFRA-positive chronic eosinophilic leukemia and T-cell lymphoblastic lymphoma: a bilineal clonal malignancy. Eur J Haematol. 2007;80(1):81–6.

    PubMed  Google Scholar 

  22. Safley AM, Sebastian S, Collins TS, Tirado CA, Stenzel TT, Gong JZ, et al. Molecular and cytogenetic characterization of a novel translocation t(4;22) involving the breakpoint cluster region and platelet-derived growth factor receptor-alpha genes in a patient with a typical chronic myeloid leukemia. Genes Chromosom Cancer. 2004;40(1):44–50.

    Article  CAS  PubMed  Google Scholar 

  23. M K, Mahon GM, Cheng L, Whitehead IP. p38 MAPK-mediated activation of NF-kappaB by the RhoGEF domain of Bcr. Oncogene. 2002;21(30):4601–12.

    Article  CAS  Google Scholar 

  24. Vardiman JW, Melo JV, Baccarani M, Thiele J. Chronic Myelogenous leukemia, BCR-ABL positive. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. World Health Organization classification of tumours. Pathology and genetics or tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. p. 32–7.

    Google Scholar 

  25. Yigit N, WW W, Subramaniyam S, Mathew S, Geyer JT. BCR-PDGFRA fusion in a T lymphoblastic leukemia/lymphoma. Cancer Gene Ther. 2015;208(7–8):404–7.

    Article  CAS  Google Scholar 

  26. Curtis CE, Grand FH, Musto P, Clark A, Murphy J, Perla G, et al. Two novel imatinib-responsive PDGRFA fusion genes in chronic eosinophilic leukaemia. Br J Haematol. 2007;138(1):77–81.

    Article  CAS  PubMed  Google Scholar 

  27. Hwang J, Pallas DC. STRIPAK complexes: structure, biological function, and involvement in human disease. Int J Biochem Cell Biol. 2014;47:118–48.

    Article  CAS  PubMed  Google Scholar 

  28. Musto P, Falcone A, Sanpaolo G, Bodenizza C, Perla G, Minervini MM, et al. Heterogeneity of response to imatinib-mesylate (Glivec) in patients with hypereosinophilic syndrome: implications for dosing and pathogenesis. Leuk Lymphoma. 2004;45(6):1219–22.

    Article  CAS  PubMed  Google Scholar 

  29. Fong K, Choi Y, Rattner JB, Qi RZ. CDK5RAP2 is a Pericentriolar protein that functions in centrosomal attachment of the γ-tubulin ring complex. Mol Biol Cell. 2008;19(1):115–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tan CA, Topper S, Ward Melver C, Stein J, Reeder A, Arndt K, et al. The first case of CDK5RAP2-related primary microcephaly in a non-consanguineous patient identified by next generation sequencing. Brain Dev. 2014;36(4):351–5.

    Article  PubMed  Google Scholar 

  31. Walz C, Curtis C, Schnittger S, Schultheis B, Metzgeroth G, Schoch C, et al. Transient response to imatinib in a chronic eosinophilic leukemia associated with ins(9;4)(q33;q12q25) and a CKD5RAP2-PDGFRA fusion Gene. Genes Chromosom Cancer. 2006;45(10):950–6.

    Article  CAS  PubMed  Google Scholar 

  32. Score J, Curtis C, Waghorn K, Stalder M, Jotterand M, Grand FH, et al. Identification of a novel imatinib responsive KIF5B-PDGFRA fusion gene following screening for PDGFRA overexpression in patients with hypereosinophilia. Leukemia. 2006;20(5):827–32.

    Article  CAS  PubMed  Google Scholar 

  33. Sugimoto Y, Sada A, Shimokariya Y, Monma F, Ohishi K, Masuya M, et al. A novel FOXP1-PDGFRA fusion gene in myeloproliferative neoplasm with eosinophilia. Cancer Gene Ther. 2015;208(10):508–12.

    Article  CAS  Google Scholar 

  34. Elling C, Erben P, Walz C, Frickenhaus M, Schemionek M, Stehling M, et al. Novel imatinib sensitive PDGRFA-activating point mutations in hypereosinophilic syndrome induce growth factor independence and leukemia-like disease. Blood. 2011;117(10):2935–43.

    Article  CAS  PubMed  Google Scholar 

  35. La Starza R, Specchia G, Cuneo A, Beacci D, Nozzoli C, Luciano L, et al. The hypereosinophilic syndrome: fluorescence in situ hybridization detects the del(4)(q12)-FIP1L1/PDGFRA but not other genomic rearrangements of other tyrosine kinases. Haematologica. 2005;90(5):596–601.

    PubMed  Google Scholar 

  36. Vandenberghe P, Wlodarska I, Michaux L, Zachée P, Boogaerts M, Vanstraelen D, et al. Clinical and molecular features of FIP1L1-PDGFRA (+) chronic eosinophilic leukemias. Leukemia. 2004;18(4):734–42.

    Article  CAS  PubMed  Google Scholar 

  37. Legrand F, Renneville A, Macintyre E, Mastrilli S, Ackermann F, Cayuela JM, et al. The spectrum of FIP1L1-PDGFRA-associated chronic eosinophilic leukemia: new insights based on a survey of 44 cases. Medicine (Baltimore). 2013;92(5):e1–9.

    Article  CAS  Google Scholar 

  38. Pardanani A, D'Souza A, Knudson RA, Hanson CA, Ketterling RP, Tefferi A. Long-term follow-up of FIP1L1-PDGFRA-mutated patients with eosinophilia: survival and clinical outcome. Leukemia. 2012;26(11):2439–41.

    Article  CAS  PubMed  Google Scholar 

  39. von Bubnoff N, Gorantla SP, Engh RA, Oliveira TM, Thöne S, Aberg E, et al. The low frequency of clinical resistance to PDGFR inhibitors in myeloid neoplasms with abnormalities of PDGFRA might be related to the limited repertoire of possible PDGFRA kinase domain mutations in vitro. Oncogene. 2011;30(8):933–43.

    Article  CAS  Google Scholar 

  40. Shen Y, Shi X, Pan J. The conformational control inhibitor of tyrosine kinases DCC-2036 is effective for imatinib-resistant cells expressing T674I FIP1L1-PDGFRα. PLoS One. 2013;8(8):e73059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Metzgeroth G, Erben P, Martin H, Mousset S, Teichmann M, Walz C, et al. Limited clinical activity of nilotinib and sorafenib in FIP1L1-PDGFRA positive chronic eosinophilic leukemia with imatinib-resistant T674I mutation. Leukemia. 2012;26(1):162–4.

    Article  CAS  PubMed  Google Scholar 

  42. Lierman E, Michaux L, Beullens E, Pierre P, Marynen P, Cools J, et al. FIP1L1-PDGFRα D842V, a novel panresistant mutant, emerging after treatment of FIP1L1-PDGFRα T674I eosinophilic leukemia with single agent sorafenib. Leukemia. 2009;23(5):845–51.

    Article  CAS  PubMed  Google Scholar 

  43. Score J, Walz C, Jovanovic JV, Jones AV, Waghorn K, Hidalgo-Curtis C, et al. Detection and molecular monitoring of FIP1L1-PDGFRA-positive disease by analysis of patient-specific genomic DNA fusion junctions. Leukemia. 2009;23(2):332–9.

    Article  CAS  PubMed  Google Scholar 

  44. Somin D, Salemi S, Yousefi S, Simon HU. Primary resistance to imatinib in Fip-like 1-platelet-derived growth factor receptor α- positive eosinophilic leukemia. J Allergy Clin Immunol. 2008;121(4):1054–6.

    Article  CAS  Google Scholar 

  45. Salemi S, Yousefi S, Simon D, Schmid I, Moretti L, Scapozza L, et al. A novel FIP1L1-PDGFRA mutant destabilizing the inactive conformation of the kinase domain in chronic eosinophilic leukemia/hypereosinophilic syndrome. Allergy. 2009;64(6):913–8.

    Article  CAS  PubMed  Google Scholar 

  46. Huang Q, Snyder DS, Chu P, Gaal KK, Chang KL, Weiss LM. PDGFRA rearrangement leading to hyper-eosinophilia, T-lymphoblastic lymphoma, myeloproliferative neoplasm and precursor B-cell acute lymphoblastic leukemia. Leukemia. 2011;25(2):371–5.

    Article  CAS  PubMed  Google Scholar 

  47. Montano-Almendras CP, Essaghir A, Schoemans H, Varis I, Noël LA, Velghe AI, et al. ETV6-PDGFRB and FIP1L1-PDGFRA stimulate human hematopoietic progenitor cell proliferation and differentiation into eosinophils: the role of nuclear factor-κB. Haematologica. 2012;97(7):1064–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor-beta to a novel Ets-like gene, Tel, in chronic myelomonocytic leukemia with t(512) chromosomal translocation. Cell. 1994;77(2):307–16.

    Article  CAS  PubMed  Google Scholar 

  49. Vega F, Medeiros LJ, Bueso-Ramos CE, Arboleda P, Miranda RN. Hematolymphoid neoplasms associated with rearrangements of PDGFRA, PDGFRB, and FGFR1. Am J Clin Pathol. 2015;144(3):377–92.

    Article  CAS  PubMed  Google Scholar 

  50. Jones AV, Cross NC. Oncogenic derivatives of platelet-derived growth factor receptors. Cell Mol Life Sci. 2004;61(23):2912–23.

    Article  CAS  PubMed  Google Scholar 

  51. Curtis CE, Grand FH, Waghorn K, Sahoo TP, George J, Cross NC. A novel ETV6-PDGFRB fusion transcript missed by standard screening in a patient with an imatinib responsive chronic myeloproliferative disease. Leukemia. 2007;21(8):1839–41.

    Article  CAS  PubMed  Google Scholar 

  52. Gosenca D, Kellert B, Metzgeroth G, Haferlach C, Fabarius A, Schwaab J, et al. Identification and functional characterization of imatinib-sensitive DTD1-PDGFRB and CCDC88C-PDGFRB fusion genes in eosinophilia-associated myeloid/lymphoid neoplasms. Genes Chromosom Cancer. 2014;53(5):411–21.

    Article  CAS  PubMed  Google Scholar 

  53. Chmielecki J, Peifer M, Viale A, Hutchinson K, Giltnane J, Socci ND, et al. Systematic screen for tyrosine kinase rearrangements identifies a novel C6orf204-PDGFRB fusion in a patient with recurrent T-ALL and an associated myeloproliferative neoplasm. Genes Chromosom Cancer. 2012;51(1):54–65.

    Article  CAS  PubMed  Google Scholar 

  54. Walz C, Metzgeroth G, Haferlach C, Schmitt-Graeff A, Fabarius A, Hagen V, et al. Characterization of three new imatinib-responsive fusion genes in chronic myeloproliferative disorders generated by disruption of the platelet-derived growth factor receptor beta gene. Haematologica. 2007;92(2):163–9.

    Article  CAS  PubMed  Google Scholar 

  55. Chen J, Williams IR, Kutok JL, Duclos N, Anastasiadou E, Masters SC, et al. Positive and negative regulatory roles of the WW-like domain in TEL-PDGFbetaR transformation. Blood. 2004;104(2):535–42.

    Article  CAS  PubMed  Google Scholar 

  56. Carroll M, Tomasson MH, Barker GF, Golub TR, Gilliland DG. The TEL/platelet-derived growth factor beta receptor (PDGF beta R) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGF beta R kinase-dependent signaling pathways. Proc Natl Acad Sci U S A. 1996;93(25):14845–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. J S, Anastasiadou E, Cain D, Kutok J, Wojiski S, Williams IR, et al. H4(D10S170), a gene frequently rearranged in papillary thyroid carcinoma, is fused to the platelet-derived growth factor receptor beta gene in atypical chronic myeloid leukemia with t(5;10)(q33;q22). Blood. 2001;97(12):3910–8.

    Article  Google Scholar 

  58. Abe A, Emi N, Tanimoto M, Terasaki H, Marunouchi T, Saito H. Fusion of the platelet-derived growth factor receptor beta to a novel gene CEV14 in acute myelogenous leukemia after clonal evolution. Blood. 1997;90(11):4271–7.

    CAS  PubMed  Google Scholar 

  59. Ross TS, Gilliland DG. Transforming properties of the Huntingtin interacting protein 1/ platelet-derived growth factor beta receptor fusion protein. J Biol Chem. 1999;274(32):22328–36.

    Article  CAS  PubMed  Google Scholar 

  60. Cavazzini F, Bardi A, Ciccone M, Rigolin GM, Gorello P, La Starza R, et al. Trisomy 8 in PDGFRB-negative cells in a patient with imatinib-sensitive chronic myelomonocytic leukemia and t(5;16)(q33;p13), PDGFRB-NDE1 fusion. Cancer Genet Cytogenet. 2009;194(1):67–9.

    Article  CAS  PubMed  Google Scholar 

  61. Keene P, Mendelow B, Pinto MR, Bezwoda W, MacDougall L, Falkson G, et al. Abnormalities of chromosome 12p 13 and malignant proliferation of eosinophils: a nonrandom association. Br J Haematol. 1987;67(1):25–31.

    Article  CAS  PubMed  Google Scholar 

  62. Levine RL, Wadleigh M, Sternberg DW, Wlodarska I, Galinsky I, Stone RM, et al. KIAA1509 is a novel PDGFRB fusion partner in imatinib-responsive myeloproliferative disease associated with a t(5;14)(q33;q32). Leukemia. 2005;19(1):27–30.

    Article  CAS  PubMed  Google Scholar 

  63. Albano F, Anelli L, Zagaria A, Lonoce A, La Starza R, Liso V, et al. Extramedullary molecular evidence of the 5′KIAA1509/3′PDGFRB fusion gene in chronic eosinophilic leukemia. Leuk Res. 2008;32(2):347–51.

    Article  CAS  PubMed  Google Scholar 

  64. Wang JR, Yen CC, Gau JP, Hsiao LT, Liu CY, Pai JT, et al. A case of myeloid neoplasm associated with eosinophilia and KIAA1509-PDGFRβ responsive to combination treatment with imatinib mesylate and prednisolone. J Clin Pharm Ther. 2010;35(6):733–6.

    Article  PubMed  Google Scholar 

  65. Kulkarni S, Heath C, Parker S, Chase A, Iqbal S, Pocock CF, et al. Fusion of H4/D10S170 to the platelet-derived growth factor receptor β in BCR-ABL-negative myeloproliferative disorders with a t(5;10)(q33;q21). Cancer Res. 2000;60(13):3592–8.

    CAS  PubMed  Google Scholar 

  66. Drechsler M, Hildebrandt B, Kündgen A, Germing U, Royer-Pokora B. Fusion of H4/D10S170 to PDGFRbeta in a patient with chronic myelomonocytic leukemia and long-term responsiveness to imatinib. Ann Hematol. 2007;86(5):353–4.

    Article  PubMed  Google Scholar 

  67. Garcia JL, Font de Mora J, Hernandez JM, Queizan JA, Gutierrez NC, Hernandez JM, et al. Imatinib mesylate elicits positive clinical response in atypical chronic myeloid leukemia involving the platelet-derived growth factor receptor beta. Blood. 2003;102(7):2699–700.

    Article  CAS  PubMed  Google Scholar 

  68. Bastie JN, Garcia I, Terré C, Cross NC, Mahon FX, Castaigne S. Lack of response to imatinib mesylate in a patient with accelerated phase myeloproliferative disorder with rearrangement of the platelet-derived growth factor receptor beta-gene. Acta Haematol. 2002;107(2):113–22.

    Article  Google Scholar 

  69. Tong Q, Li Y, Smanik PA, Fithian LJ, Xing S, Mazzaferri EL, et al. Characterization of the promoter region and oligomerization domain of H4 (D10S170), a gene frequently rearranged with the ret proto-oncogene. Oncogene. 1995;10(9):1781–7.

    CAS  PubMed  Google Scholar 

  70. Kim HG, Jang JH, Koh EH. TRIP11-PDGFRB fusion in a patient with a therapy-related myeloid neoplasm with t(5;14)(q33;q32) after treatment for acute promyelocytic leukemia. Mol Cytogenet. 2014;7(1):103.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Gong SL, Guo MQ, Tang GS, Zhang CL, Qiu HY, XX H, et al. Fusion of platelet-derived growth factor receptor β to CEV14 gene in chronic myelomonocytic leukemia: a case report and review of the literature. Oncol Lett. 2016;11(1):770–4.

    PubMed  Google Scholar 

  72. Abe A, Tanimoto M, Towatari M, Matsuoka A, Kitaori K, Kato H, et al. Acute myeloblastic leukemia (M2) with translocation (7;11) followed by marked eosinophilia and additional abnormalities of chromosome 5. Cancer Genet Cytogenet. 1995;83(1):37–41.

    Article  CAS  PubMed  Google Scholar 

  73. Ríos RM, Sanchís A, Tassin AM, Fedriani C, Bornens M. GMAP-210 recruits gamma-tubulin complexes to cis-Golgi membranes and is required for Golgi ribbon formation. Cell. 2004;118(3):323–35.

    Article  PubMed  Google Scholar 

  74. Rosati R, La Starza R, Luciano L, Gorello P, Matteucci C, Pierini V, et al. TPM3/PDGFRB fusion transcript and its reciprocal in chronic eosinophilic leukemia. Leukemia. 2006;20(9):1623–4.

    Article  CAS  PubMed  Google Scholar 

  75. Li Z, Yang R, Zhao J, Yuan R, Lu Q, Li Q, et al. Molecular diagnosis and targeted therapy of a pediatric chronic eosinophilic leukemia patient carrying TPM3-PDGFRB fusion. Pediatr Blood Cancer. 2011;56(3):463–6.

    Article  PubMed  Google Scholar 

  76. Chang H, Chuang WY, Sun CF, Barnard MR. Concurrent acute myeloid leukemia and T lymphoblastic lymphoma in a patient with rearranged PDGFRB genes. Diagn Pathol. 2012;7:19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ondrejka SL, Jegalian AG, Kim AS, Chabot-Richards DS, Giltnane J, Czuchlewski DR, et al. PDGFRB-rearranged T-lymphoblastic leukemia/lymphoma occurring with myeloid neoplasms: the missing link supporting a stem cell origin. Haematologica. 2014;99(9):e148–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Magnusson MK, Meade KE, Brown KE, Arthur DC, Krueger LA, et al. Rabaptin-5 is a novel fusion partner to platelet-derived growth factor beta receptor in chronic myelomonocytic leukemia. Blood. 2001;98(8):2518–25.

    Article  CAS  PubMed  Google Scholar 

  79. Winkelmann N, Hidalgo-Curtis C, Waghorn K, Score J, Dickinson H, Jack A, et al. Recurrent CEP85L-PDGFRB fusion in patient with t(5;6) and imatinib-responsive myeloproliferative neoplasm with eosinophilia. Leuk Lymphoma. 2013;54(7):1527–31.

    Article  CAS  PubMed  Google Scholar 

  80. Lahortiga I, Akin C, Cools J, Wilson TM, Mentens N, Arthur DC, et al. Activity of imatinib in systemic mastocytosis with chronic basophilic leukemia and a PRKG2-PDGFRB fusion. Haematologica. 2008;93(1):49–56.

    Article  CAS  PubMed  Google Scholar 

  81. Gallagher G, Horsman DE, Tsang P, Forrest DL. Fusion of PRKG2 and SPTBN1 to the platelet-derived growth factor receptor beta gene (PDGFRB) in imatinib-responsive atypical myeloproliferative disorders. Cancer Genet Cytogenet. 2008;181(1):46–51.

    Article  CAS  PubMed  Google Scholar 

  82. Arefi M, García JL, Peñarrubia MJ, Queizán JA, Hermosín L, López-Corral L, et al. Incidence and clinical characteristics of myeloproliferative neoplasms displaying a PDGFRB rearrangement. Eur J Haematol. 2012;89(1):37–41.

    Article  CAS  PubMed  Google Scholar 

  83. Stover DA, Verrelli BC. Comparative vertebrate evolutionary analyses of type I collagen: potential of COL1a1 gene structure and intron variation for common bone-related diseases. Mol Biol Evol. 2011;28(1):533–42.

    Article  CAS  PubMed  Google Scholar 

  84. Folens C, Cools J, Marynen P, Martelli MF, Mecucci C, Cuneo A. A new NDE1/PDGFRB fusion transcript underlying chronic myelomonocytic leukaemia in Noonan Syndrome. Leukemia. 2007;21(4):830–3.

    PubMed  Google Scholar 

  85. Wilkinson K, Velloso ER, Lopes LF, Lee C, Aster JC, Shipp MA, et al. Cloning of the t(1;5)(q23;q33) in a myeloproliferative disorder associated with eosinophilia: involvement of PDGFRB and response to imatinib. Blood. 2003;102(12):4187–90.

    Article  CAS  PubMed  Google Scholar 

  86. Grand FH, Burgstaller S, Kühr T, Baxter EJ, Webersinke G, Thaler J, et al. p53-Binding protein 1 is fused to the platelet-derived growth factor receptor beta in a patient with a t(5;15)(q33;q22) and an imatinib-responsive eosinophilic myeloproliferative disorder. Cancer Res. 2004;64(20):7216–9.

    Article  CAS  PubMed  Google Scholar 

  87. Morerio C, Acquila M, Rosanda C, Rapella A, Dufour C, Locatelli F, et al. HCMOGT-1 is a novel fusion partner to PDGFRB in juvenile myelomonocytic leukemia with t(5;17)(q33;p11.2). Cancer Res. 2004;64(8):2649–51.

    Article  CAS  PubMed  Google Scholar 

  88. Hidalgo-Curtis C, Apperley JF, Stark A, Jeng M, Gotlib J, Chase A, et al. Fusion of PDGFRB to two distinct loci at 3p21 and a third at 12q13 in imatinib-responsive myeloproliferative neoplasms. Br J Haematol. 2010;148(2):268–73.

    Article  CAS  PubMed  Google Scholar 

  89. Ross TS, Bernard OA, Berger R, Gilliland DG. Fusion of Huntingtin interacting protein 1 to platelet-derived growth factor beta receptor (PDGFbetaR) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2). Blood. 1998;91(12):4419–26.

    CAS  PubMed  Google Scholar 

  90. Niu Q, Ybe JA. Crystal structure at 2.8 A of Huntingtin-interacting protein 1 (HIP1) coiled-coil domain reveals a charged surface suitable for HIP-protein interactor (HIPPI). J Mol Biol. 2008;375(5):1197–205.

    Article  CAS  PubMed  Google Scholar 

  91. Walz C, Haferlach C, Hänel A, Metzgeroth G, Erben P, Gosenca D, et al. Identification of a MYO18A-PDGFRB fusion gene in an eosinophilia-associated atypical myeloproliferative neoplasm with a t(5;17)(q33-34;q11.2). Genes Chromosom Cancer. 2009 Feb;48(2):179–83.

    Article  CAS  PubMed  Google Scholar 

  92. Vizmanos JL, Novo FJ, Román JP, Baxter EJ, Lahortiga I, Larráyoz MJ, et al. NIN, a gene encoding a CEP110-like centrosomal protein, is fused to PDGFRB in a patient with a t(5;14)(q33;q24) and an imatinib-responsive myeloproliferative disorder. Cancer Res. 2004;64(8):2673–6.

    Article  CAS  PubMed  Google Scholar 

  93. Erben P, Gosenca D, Müller MC, Reinhard J, Score J, Del Valle F, et al. Screening for diverse PDGFRA or PDGFRB fusion genes is facilitated by generic quantitative reverse transcriptase polymerase chain reaction analysis. Haematologica. 2010;95(5):738–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gorello P, La Starza R, Brandimarte L, Trisolini SM, Pierini V, Crescenzi B, et al. A PDGFRB-positive acute myeloid malignancy with a new t(5;12)(q33;p13.3) involving the ERC1 gene. Leukemia. 2008;22(1):216–8.

    Article  CAS  PubMed  Google Scholar 

  95. Medves S, Duhoux FP, Ferrant A, Toffalini F, Ameye G, Libouton JM, et al. KANK1, a candidate tumor suppressor gene, is fused to PDGFRB in an imatinib-responsive myeloid neoplasm with severe thrombocythemia. Leukemia. 2010;24(5):1052–5.

    Article  CAS  PubMed  Google Scholar 

  96. Baxter EJ, Kulkarni S, Vizmanos JL, Jaju R, Martinelli G, Testoni N, et al. Novel translocations that disrupt the platelet-derived growth factor receptor beta (PDGFRB) gene in BCR-ABL-negative chronic myeloproliferative disorders. Br J Haematol. 2003;120(2):251–6.

    Article  CAS  PubMed  Google Scholar 

  97. Cheah CY, Burbury K, Apperley JF, Huguet F, Pitini V, Gardembas M, et al. Patients with myeloid malignancies bearing PDGFRB fusion genes achieve durable long-term remissions with imatinib. Blood. 2014;123(23):3574–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Cerrano M, Crisà E, Gottardi E, Aguzzi C, Boccadoro M, Ferrero D. Long-term therapy-free remission in a patient with platelet-derived growth factor receptor beta (PDGFRB)-rearranged myeloproliferative neoplasm. Am J Hematol. 2016;91(9):E353. [Epub ahead of print]

    Article  PubMed  Google Scholar 

  99. Macdonald D, Aguiar RC, Mason PJ, Goldman JM, Cross NC. A new myeloproliferative disorder associated with chromosomal translocations involving 8p11: a review. Leukemia. 1995;9(10):1628–30.

    CAS  PubMed  Google Scholar 

  100. Jackson CC, Medeiros LJ, Miranda RN. 8p11 myeloproliferative syndrome: a review. Hum Pathol. 2010;41(4):461–76.

    Article  CAS  PubMed  Google Scholar 

  101. Manthorpe R, Egeberg J, Hesselvik M, Videbaek A. Unique eosinophil granules in a case of T-cell lymphoma. Scand J Haematol. 1977;19(2):129–44.

    Article  CAS  PubMed  Google Scholar 

  102. Kuskonmaz B, Kafali C, Akcoren Z, Karabulut HG, Akalin I, Tuncer MA. The 8p11 myeloproliferative syndrome in a 3-year-old child. Leuk Res. 2008;32(1):198–9.

    Article  CAS  PubMed  Google Scholar 

  103. Friedhoff F, Rajendra B, Moody R, Alapatt T. Novel reciprocal translocation between chromosomes 8 and 9 found in a patient with myeloproliferative disorder. Cancer Genet Cytogenet. 1983;9(4):391–4.

    Article  CAS  PubMed  Google Scholar 

  104. Patnaik MM, Gangat N, Knudson RA, Keefe JG, Hanson CA, Pardanani A, et al. Chromosome 8p11.2 translocations: prevalence, FISH analysis for FGFR1 and MYST3, and clinicopathologic correlates in a consecutive cohort of 13 cases from a single institution. Am J Hematol. 2010;85(4):238–42.

    Article  CAS  PubMed  Google Scholar 

  105. Savage NM, Johnson RC, Gotlib J, George TI. Myeloid and lymphoid neoplasms with FGFR1 abnormalities: diagnostic and therapeutic challenges. Am J Hematol. 2013;88(5):427–30.

    Article  CAS  PubMed  Google Scholar 

  106. Demiroglu A, Steer EJ, Heath C, Taylor K, Bentley M, Allen SL, et al. The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: transforming activity and specific inhibition of FGFR1 fusion proteins. Blood. 2001;98(13):3778–83.

    Article  CAS  PubMed  Google Scholar 

  107. Popovici C, Zhang B, Grégoire MJ, Jonveaux P, Lafage-Pochitaloff M, Birnbaum D, et al. The t(6;8)(q27;p11) translocation in a stem cell myeloproliferative disorder fuses a novel gene, FOP, to fibroblast growth factor receptor 1. Blood. 1999;93(4):1381–9.

    CAS  PubMed  Google Scholar 

  108. Vizmanos JL, Hernández R, Vidal MJ, Larráyoz MJ, Odero MD, Marín J, et al. Clinical variability of patients with the t(6;8)(q27;p12) and FGFR1OP-FGFR1 fusion: two further cases. Hematol J. 2004;5(6):534–7.

    Article  CAS  PubMed  Google Scholar 

  109. Vega F, Medeiros LJ, Davuluri R, Cromwell CC, Alkan S, Abruzzo LV. t(8;13)-positive bilineal lymphomas: report of 6 cases. Am J Surg Pathol. 2008;32(1):14–20.

    Article  PubMed  Google Scholar 

  110. Hu S, He Y, Zhu X, Li J, He H. Myeloproliferative disorders with t(8;9)(p12;q33): a case report and review of the literature. Pediatr Hematol Oncol. 2011;28(2):140–6.

    Article  CAS  PubMed  Google Scholar 

  111. Guasch G, Ollendorff V, Borg JP, Birnbaum D, Pebusque MJ. 8p12 stem cell myeloproliferative disorder: the FOP-fibroblast growth factor receptor 1 fusion protein of the t(6;8) translocation induces cell survival mediated by mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt/mTOR pathways. Mol Cell Biol. 2001;21(23):8129–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Matikas A, Tzannou I, Oikonomopoulou D, Bakiri M. A case of acute myelogenous leukaemia characterised by the BCR-FGFR1 translocation. BMJ Case Rep. 2013;pii:bcr2013008834

    Google Scholar 

  113. Kim WS, Park SG, Park G, Jang SJ, Moon DS, Kang SH. 8p11 myeloproliferative syndrome with t(1;8)(q25;p11.2): a case report and review of the literature. Acta Haematol. 2015;133(1):101–5.

    Article  PubMed  Google Scholar 

  114. Mugneret F, Chaffanet M, Maynadié M, Guasch G, Favre B, Casasnovas O, et al. The 8p12 myeloproliferative disorder. t(8;19)(p12;q13.3): a novel translocation involving the FGFR1 gene. Br J Haematol. 2000;111(2):647–9.

    Article  CAS  PubMed  Google Scholar 

  115. Guasch G, Popovici C, Mugneret F, Chaffanet M, Pontarotti P, Birnbaum D, et al. Endogenous retroviral sequence is fused to FGFR1 kinase in the 8p12 stem-cell myeloproliferative disorder with t(8;19)(p12;q13.3). Blood. 2003;101(1):286–8.

    Article  CAS  PubMed  Google Scholar 

  116. Grand EK, Grand FH, Chase AJ, Ross FM, Corcoran MM, Oscier DG, et al. Identification of a novel gene, FGFR1OP2, fused to FGFR1 in 8p11 myeloproliferative syndrome. Genes Chromosom Cancer. 2004;40(1):78–83.

    Article  CAS  PubMed  Google Scholar 

  117. Belloni E, Trubia M, Gasparini P, Micucci C, Tapinassi C, Confalonieri S, et al. 8p11 myeloproliferative syndrome with a novel t(7;8) translocation leading to fusion of the FGFR1 and TIF1 genes. Genes Chromosom Cancer. 2005;42(3):320–5.

    Article  CAS  PubMed  Google Scholar 

  118. Soler G, Nusbaum S, Varet B, Macintyre EA, Vekemans M, Romana SP, et al. LRRFIP1,a new FGFR1 partner gene associated with 8p11 myeloproliferative syndrome. Leukemia. 2009;23(7):1359–61.

    Article  CAS  PubMed  Google Scholar 

  119. Walz C, Chase A, Schoch C, Weisser A, Schlegel F, Hochhaus A, et al. The t(8;17)(p11;q23) in the 8p11 myeloproliferative syndrome fuses MYO18A to FGFR1. Leukemia. 2005;19(6):1005–9.

    Article  CAS  PubMed  Google Scholar 

  120. Shvidel L, Sigler E, Vorst E, Feldberg E, Voskoboinic N, Shtalrid M, et al. A novel cytogenetic aberration found in stem cell leukemia/lymphoma syndrome. Leukemia. 2008;22(3):644–6.

    Article  CAS  PubMed  Google Scholar 

  121. Sohal J, Chase A, Mould S, Corcoran M, Oscier D, Iqbal S, et al. Identification of four new translocations involving FGFR1 in myeloid disorders. Genes Chromosom Cancer. 2001;32(2):155–63.

    Article  CAS  PubMed  Google Scholar 

  122. Bae SY, Kim JS, Han EA, Lee HJ, Ryeu BJ, Lee KN, et al. Cytogenetic abnormality involving 8p11.2 in T-lymphoblastic lymphoma: report of a new case. Cancer Genet Cytogenet. 2009;191(1):57–8.

    Article  CAS  PubMed  Google Scholar 

  123. Wasag B, Lierman E, Meeus P, Cools J, Vandenberghe P. The kinase inhibitor TKI258 is active against the novel CUX1-FGFR1 fusion detected in a patient with T-lymphoblastic leukemia/lymphoma and t(7;8)(q22;p11). Haematologica. 2011;96(6):922–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Post GR, Holloman D, Christiansen L, Smith J, Stuart R, Lazarchick J. Translocation t(3;8;9)(p25;p21;q34) in a patient with features of 8p11 myeloproliferative syndrome: a unique case and review of the literature. Leuk Res. 2010;34(11):1543–4.

    Article  CAS  PubMed  Google Scholar 

  125. Abruzzo LV, Jaffe ES, Cotelingam JD, Whang-Peng J, Del Duca V, Medeiros LJ. T-cell lymphoblastic lymphoma with eosinophilia associated with subsequent myeloid malignancy. Am J Surg Pathol. 1992;16(3):236–45.

    Article  CAS  PubMed  Google Scholar 

  126. Chen J, Deangelo DJ, Kutok JL, Williams IR, Lee BH, Wadleigh M, et al. PKC412 inhibits the zinc finger 198-fibroblast growth factor receptor 1 fusion tyrosine kinase and is active in treatment of stem cell myeloproliferative disorder. Proc Natl Acad Sci U S A. 2004;101(40):14479–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Martinez-Climent JA, Vizcarra E, Benet I, Marugan I, Terol MJ, Solano C, et al. Cytogenetic response induced by interferon alpha in the myeloproliferative disorder with eosinophilia, T cell lymphoma and the chromosomal translocation t(8;13)(p11;q12). Leukemia. 1998;12(6):999–1000.

    Article  CAS  PubMed  Google Scholar 

  128. Zhou L, Fu W, Yuan Z, Hou J. Complete molecular remission after interferon alpha treatment in a case of 8p11 myeloproliferative syndrome. Leuk Res. 2010;34(11):306–7.

    Article  Google Scholar 

  129. Ren M, Qin H, Wu Q, Savage NM, George TI, Cowell JK. Development of ZMYM2-FGFR1 driven AML in human CD34+ cells in immunocompromised mice. Int J Cancer. 2016;139(4):836–40.

    Article  CAS  PubMed  Google Scholar 

  130. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405.

    Article  CAS  PubMed  Google Scholar 

  131. Stewart K, Carstairs KC, Dubé ID, Keating A. Neutrophilic myelofibrosis presenting as Philadelphia chromosome negative BCR non-rearranged chronic myeloid leukemia. Am J Hematol. 1990;34(1):59–63.

    Article  CAS  PubMed  Google Scholar 

  132. Reiter A, Walz C, Watmore A, Schoch C, Blau I, Schlegelberger B, et al. The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2. Cancer Res. 2005;65(7):2662–7.

    Article  CAS  PubMed  Google Scholar 

  133. Bain BJ, Ahmad S. Should myeloid and lymphoid neoplasms with PCM1-JAK2 and other rearrangements of JAK2 be recognized as specific entities? Br J Haematol. 2014;166(6):809–17.

    Article  CAS  PubMed  Google Scholar 

  134. Patterer V, Schnittger S, Kern W, Haferlach T, Haferlach C. Hematologic malignancies with PCM1-JAK2 gene fusion share characteristics with myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1. Ann Hematol. 2013;92(6):759–69.

    Article  CAS  PubMed  Google Scholar 

  135. Rumi E, Milosevic JD, Selleslag D, Casetti I, Lierman E, Pietra D, et al. Efficacy of ruxolitinib in myeloid neoplasms with PCM1-JAK2 fusion gene. Ann Hematol. 2015;94(11):1927–8.

    Article  PubMed  Google Scholar 

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  1. Department of Pathology, Medical College of Georgia at Augusta University, Augusta, GA, USA

    Joanna M. Chaffin MD & Natasha M. Savage MD

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    Chung-Che (Jeff) Chang

  2. Department of Pathology, Stanford University, Stanford, California, USA

    Robert S. Ohgami

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Chaffin, J.M., Savage, N.M. (2018). Myeloid and Lymphoid Neoplasms with Eosinophilia and Abnormalities of PDGFRA, PDGFRB, FGFR1, or t(8;9)(p22;p24.1);PCM1-JAK2 . In: Chang, CC., Ohgami, R. (eds) Precision Molecular Pathology of Myeloid Neoplasms. Molecular Pathology Library, vol 12. Springer, Cham. https://doi.org/10.1007/978-3-319-62146-3_16

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