nach oben

International Journal of Hematology

Erschienen in:

01.03.2015 | Progress in Hematology

Molecular pathogenesis of atypical CML, CMML and MDS/MPN-unclassifiable

verfasst von: Katerina Zoi, Nicholas C. P. Cross

Erschienen in: International Journal of Hematology | Ausgabe 3/2015

Einloggen, um Zugang zu erhalten

Abstract

According to the 2008 WHO classification, the category of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) includes atypical chronic myeloid leukaemia (aCML), chronic myelomonocytic leukaemia (CMML), MDS/MPN-unclassifiable (MDS/MPN-U), juvenile myelomonocytic leukaemia (JMML) and a “provisional” entity, refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T). The remarkable progress in our understanding of the somatic pathogenesis of MDS/MPN has made it clear that there is considerable overlap among these diseases at the molecular level, as well as layers of unexpected complexity. Deregulation of signalling plays an important role in many cases, and is clearly linked to more highly proliferative disease. Other mutations affect a range of other essential, interrelated cellular mechanisms, including epigenetic regulation, RNA splicing, transcription, and DNA damage response. The various combinations of mutations indicate a multi-step pathogenesis, which likely contributes to the marked clinical heterogeneity of these disorders. The delineation of complex clonal architectures may serve as the cornerstone for the identification of novel therapeutic targets and lead to better patient outcomes. This review summarizes some of the current knowledge of molecular pathogenetic lesions in the MDS/MPN subtypes that are seen in adults: atypical CML, CMML and MDS/MPN-U.

Vardiman JBR, Arber DA, et al. Introduction and overview of the classification of myeloid neoplasms. In: Swerdlow SCE, Harris NL, editors. International Agency for Research on Cancer, WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue. 4th ed. Geneva: World Health Organization; 2008. p. 18–30.

Breccia M, Biondo F, Latagliata R, Carmosino I, Mandelli F, Alimena G. Identification of risk factors in atypical chronic myeloid leukemia. Haematologica. 2006;91:1566–8.PubMed

Costa R, Abdulhaq H, Haq B, Shadduck RK, Latsko J, Zenati MA, et al. Activity of azacitidine in chronic myelomonocytic leukemia. Cancer. 2011;117:2690–6.PubMed

Elliott MA, Hanson CA, Dewald GW, Smoley SA, Lasho TL, Tefferi A. WHO-defined chronic neutrophilic leukemia: a long-term analysis of 12 cases and a critical review of the literature. Leukemia. 2005;19:313–7.PubMed

Rollison DE, Howlader N, Smith MT, Strom SS, Merritt WD, Ries LA, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood. 2008;112:45–52.PubMed

Wang SA, Hasserjian RP, Fox PS, Rogers HJ, Geyer JT, Chabot-Richards D, et al. Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms. Blood. 2014;123:2645–51.PubMed

Tiu RV, Sekeres MA. Making sense of the myelodysplastic/myeloproliferative neoplasms overlap syndromes. Curr Opin Hematol. 2014;21:131–40.PubMed

Tiu RV, Gondek LP, O’Keefe CL, Elson P, Huh J, Mohamedali A, et al. Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood. 2011;117:4552–60.PubMedCentralPubMed

Burgstaller S, Reiter A, Cross NC. BCR-ABL-negative chronic myeloid leukemia. Curr Hematol Malig Rep. 2007;2:75–82.PubMed

10.

Cazzola M, Malcovati L, Invernizzi R. Myelodysplastic/myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program. 2011;2011:264–72.PubMed

11.

Aguiar RC, Chase A, Coulthard S, Macdonald DH, Carapeti M, Reiter A, et al. Abnormalities of chromosome band 8p11 in leukemia: two clinical syndromes can be distinguished on the basis of MOZ involvement. Blood. 1997;90:3130–5.PubMed

12.

Chase A, Bryant C, Score J, Cross NC. Ponatinib as targeted therapy for FGFR1 fusions associated with the 8p11 myeloproliferative syndrome. Haematologica. 2013;98:103–6.PubMedCentralPubMed

13.

Chase A, Bryant C, Score J, Haferlach C, Grossmann V, Schwaab J, et al. Ruxolitinib as potential targeted therapy for patients with JAK2 rearrangements. Haematologica. 2013;98:404–8.PubMedCentralPubMed

14.

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;123:3574–7.PubMed

15.

Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, 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;348:1201–14.PubMed

16.

Lierman E, Selleslag D, Smits S, Billiet J, Vandenberghe P. Ruxolitinib inhibits transforming JAK2 fusion proteins in vitro and induces complete cytogenetic remission in t(8;9)(p22;p24)/PCM1-JAK2-positive chronic eosinophilic leukemia. Blood. 2012;120:1529–31.PubMed

17.

Ballerini P, Struski S, Cresson C, Prade N, Toujani S, Deswarte C, et al. RET fusion genes are associated with chronic myelomonocytic leukemia and enhance monocytic differentiation. Leukemia. 2012;26:2384–9.PubMed

18.

Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28:241–7.PubMedCentralPubMed

19.

Kohlmann A, Grossmann V, Nadarajah N, Haferlach T. Next-generation sequencing—feasibility and practicality in haematology. Br J Haematol. 2013;160:736–53.PubMed

20.

Score J, Cross NC. Acquired uniparental disomy in myeloproliferative neoplasms. Hematol Oncol Clin North Am. 2012;26:981–91.PubMed

21.

Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet. 2010;42:722–6.PubMed

22.

Grand FH, Hidalgo-Curtis CE, Ernst T, Zoi K, Zoi C, McGuire C, et al. Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood. 2009;113:6182–92.PubMed

23.

Score J, Hidalgo-Curtis C, Jones AV, Winkelmann N, Skinner A, Ward D, et al. Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms. Blood. 2012;119:1208–13.PubMed

24.

Kon A, Shih LY, Minamino M, Sanada M, Shiraishi Y, Nagata Y, et al. Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. Nat Genet. 2013;45:1232–7.PubMed

25.

Piazza R, Valletta S, Winkelmann N, Redaelli S, Spinelli R, Pirola A, et al. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet. 2013;45:18–24.PubMedCentralPubMed

26.

Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478:64–9.PubMed

27.

Itzykson R, Kosmider O, Renneville A, Gelsi-Boyer V, Meggendorfer M, Morabito M, et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol. 2013;31:2428–36.PubMed

28.

Padron E, Painter JS, Kunigal S, Mailloux AW, McGraw K, McDaniel JM, et al. GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia. Blood. 2013;121:5068–77.PubMed

29.

Braun BS, Tuveson DA, Kong N, Le DT, Kogan SC, Rozmus J, et al. Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc Natl Acad Sci USA. 2004;101:597–602.PubMedCentralPubMed

30.

Chan IT, Kutok JL, Williams IR, Cohen S, Kelly L, Shigematsu H, et al. Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease. J Clin Invest. 2004;113:528–38.PubMedCentralPubMed

31.

Van Meter ME, Diaz-Flores E, Archard JA, Passegue E, Irish JM, Kotecha N, et al. K-RasG12D expression induces hyperproliferation and aberrant signaling in primary hematopoietic stem/progenitor cells. Blood. 2007;109:3945–52.PubMedCentralPubMed

32.

Sabnis AJ, Cheung LS, Dail M, Kang HC, Santaguida M, Hermiston ML, et al. Oncogenic Kras initiates leukemia in hematopoietic stem cells. PLoS Biol. 2009;7:e59.PubMed

33.

Itzykson R, Kosmider O, Renneville A, Morabito M, Preudhomme C, Berthon C, et al. Clonal architecture of chronic myelomonocytic leukemias. Blood. 2013;121:2186–98.PubMed

34.

Ricci C, Fermo E, Corti S, Molteni M, Faricciotti A, Cortelezzi A, et al. RAS mutations contribute to evolution of chronic myelomonocytic leukemia to the proliferative variant. Clin Cancer Res. 2010;16:2246–56.PubMed

35.

Fend F, Horn T, Koch I, Vela T, Orazi A. Atypical chronic myeloid leukemia as defined in the WHO classification is a JAK2 V617F negative neoplasm. Leuk Res. 2008;32:1931–5.PubMed

36.

Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood. 2005;106:2162–8.PubMed

37.

Levine RL, Loriaux M, Huntly BJ, Loh ML, Beran M, Stoffregen E, et al. The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood. 2005;106:3377–9.PubMedCentralPubMed

38.

Malcovati L, Della Porta MG, Pietra D, Boveri E, Pellagatti A, Galli A, et al. Molecular and clinical features of refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Blood. 2009;114:3538–45.PubMed

39.

Raya JM, Arenillas L, Domingo A, Bellosillo B, Gutierrez G, Luno E, et al. Refractory anemia with ringed sideroblasts associated with thrombocytosis: comparative analysis of marked with non-marked thrombocytosis, and relationship with JAK2 V617F mutational status. Int J Hematol. 2008;88:387–95.PubMed

40.

Szpurka H, Tiu R, Murugesan G, Aboudola S, Hsi ED, Theil KS, et al. Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation. Blood. 2006;108:2173–81.PubMedCentralPubMed

41.

Cross NC. Genetic and epigenetic complexity in myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program. 2011;2011:208–14.PubMed

42.

Oh ST, Gotlib J. JAK2 V617F and beyond: role of genetics and aberrant signaling in the pathogenesis of myeloproliferative neoplasms. Expert Rev Hematol. 2010;3:323–37.PubMed

43.

Szpurka H, Gondek LP, Mohan SR, Hsi ED, Theil KS, Maciejewski JP. UPD1p indicates the presence of MPL W515L mutation in RARS-T, a mechanism analogous to UPD9p and JAK2 V617F mutation. Leukemia. 2009;23:610–4.PubMed

44.

Kohlmann A, Grossmann V, Klein HU, Schindela S, Weiss T, Kazak B, et al. Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic myelomonocytic leukemia by detecting frequent alterations in TET2, CBL, RAS, and RUNX1. J Clin Oncol. 2010;28:3858–65.PubMed

45.

Makishima H, Cazzolli H, Szpurka H, Dunbar A, Tiu R, Huh J, et al. Mutations of e3 ubiquitin ligase cbl family members constitute a novel common pathogenic lesion in myeloid malignancies. J Clin Oncol. 2009;27:6109–16.PubMedCentralPubMed

46.

Sanada M, Suzuki T, Shih LY, Otsu M, Kato M, Yamazaki S, et al. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature. 2009;460:904–8.PubMed

47.

Valent P, Arock M, Akin C, Sperr WR, Reiter A, Sotlar K, et al. The classification of systemic mastocytosis should include mast cell leukemia (MCL) and systemic mastocytosis with a clonal hematologic non-mast cell lineage disease (SM-AHNMD). Blood. 2010;116:850–1.PubMedCentralPubMed

48.

Longley BJ Jr, Metcalfe DD, Tharp M, Wang X, Tyrrell L, Lu SZ, et al. Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc Natl Acad Sci USA. 1999;96:1609–14.PubMedCentralPubMed

49.

Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG, et al. Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nat Genet. 1996;12:312–4.PubMed

50.

Lennartsson J, Ronnstrand L. Stem cell factor receptor/c-Kit: from basic science to clinical implications. Physiol Rev. 2012;92:1619–49.PubMed

51.

Machherndl-Spandl S, Sega W, Bosmuller H, Germing U, Gruber C, Nachtkamp K, et al. Prognostic impact of blast cell counts in dysplastic bone marrow disorders (MDS and CMML I) with concomitant fibrosis. Ann Hematol. 2014;93:57–64.PubMed

52.

Sotlar K, Marafioti T, Griesser H, Theil J, Aepinus C, Jaussi R, et al. Detection of c-kit mutation Asp 816 to Val in microdissected bone marrow infiltrates in a case of systemic mastocytosis associated with chronic myelomonocytic leukaemia. Mol Pathol. 2000;53:188–93.PubMedCentralPubMed

53.

Daver N, Strati P, Jabbour E, Kadia T, Luthra R, Wang S, et al. FLT3 mutations in myelodysplastic syndrome and chronic myelomonocytic leukemia. Am J Hematol. 2013;88:56–9.PubMedCentralPubMed

54.

Lin P, Jones D, Medeiros LJ, Chen W, Vega-Vazquez F, Luthra R. Activating FLT3 mutations are detectable in chronic and blast phase of chronic myeloproliferative disorders other than chronic myeloid leukemia. Am J Clin Pathol. 2006;126:530–3.PubMed

55.

Grand FH, Iqbal S, Zhang L, Russell NH, Chase A, Cross NC. A constitutively active SPTBN1-FLT3 fusion in atypical chronic myeloid leukemia is sensitive to tyrosine kinase inhibitors and immunotherapy. Exp Hematol. 2007;35:1723–7.PubMed

56.

Walz C, Erben P, Ritter M, Bloor A, Metzgeroth G, Telford N, et al. Response of ETV6-FLT3-positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3. Blood. 2011;118:2239–42.PubMed

57.

Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100:1532–42.PubMed

58.

Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3:650–65.PubMed

59.

Lee BH, Tothova Z, Levine RL, Anderson K, Buza-Vidas N, Cullen DE, et al. FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia. Cancer Cell. 2007;12:367–80.PubMedCentralPubMed

60.

Maxson JE, Gotlib J, Pollyea DA, Fleischman AG, Agarwal A, Eide CA, et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med. 2013;368:1781–90.PubMedCentralPubMed

61.

Pardanani A, Lasho TL, Laborde RR, Elliott M, Hanson CA, Knudson RA, et al. CSF3R T618I is a highly prevalent and specific mutation in chronic neutrophilic leukemia. Leukemia. 2013;27:1870–3.PubMedCentralPubMed

62.

Beekman R, Touw IP. G-CSF and its receptor in myeloid malignancy. Blood. 2010;115:5131–6.PubMed

63.

Liu F, Wu HY, Wesselschmidt R, Kornaga T, Link DC. Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice. Immunity. 1996;5:491–501.PubMed

64.

Mitsui T, Watanabe S, Taniguchi Y, Hanada S, Ebihara Y, Sato T, et al. Impaired neutrophil maturation in truncated murine G-CSF receptor-transgenic mice. Blood. 2003;101:2990–5.PubMed

65.

Corey SJ, Burkhardt AL, Bolen JB, Geahlen RL, Tkatch LS, Tweardy DJ. Granulocyte colony-stimulating factor receptor signaling involves the formation of a three-component complex with Lyn and Syk protein-tyrosine kinases. Proc Natl Acad Sci USA. 1994;91:4683–7.PubMedCentralPubMed

66.

Corey SJ, Dombrosky-Ferlan PM, Zuo S, Krohn E, Donnenberg AD, Zorich P, et al. Requirement of Src kinase Lyn for induction of DNA synthesis by granulocyte colony-stimulating factor. J Biol Chem. 1998;273:3230–5.PubMed

67.

Futami M, Zhu QS, Whichard ZL, Xia L, Ke Y, Neel BG, et al. G-CSF receptor activation of the Src kinase Lyn is mediated by Gab2 recruitment of the Shp2 phosphatase. Blood. 2011;118:1077–86.PubMedCentralPubMed

68.

Gotlib J, Maxson JE, George TI, Tyner JW. The new genetics of chronic neutrophilic leukemia and atypical CML: implications for diagnosis and treatment. Blood. 2013;122:1707–11.PubMedCentralPubMed

69.

Fleischman AG, Maxson JE, Luty SB, Agarwal A, Royer LR, Abel ML, et al. The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in mice that is responsive to therapeutic JAK inhibition. Blood. 2013;122:3628–31.PubMedCentralPubMed

70.

Tefferi A, Thiele J, Vannucchi AM, Barbui T. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms. Leukemia. 2014;7:1407–13.

71.

Beekman R, Valkhof MG, Sanders MA, van Strien PM, Haanstra JR, Broeders L, et al. Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia. Blood. 2012;119:5071–7.PubMed

72.

Skokowa J, Steinemann D, Katsman-Kuipers JE, Zeidler C, Klimenkova O, Klimiankou M, et al. Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis. Blood. 2014;123:2229–37.PubMed

73.

Kosmider O, Itzykson R, Chesnais V, Lasho T, Laborde R, Knudson R, et al. Mutation of the colony-stimulating factor-3 receptor gene is a rare event with poor prognosis in chronic myelomonocytic leukemia. Leukemia. 2013;27:1946–9.PubMed

74.

Damm F, Itzykson R, Kosmider O, Droin N, Renneville A, Chesnais V, et al. SETBP1 mutations in 658 patients with myelodysplastic syndromes, chronic myelomonocytic leukemia and secondary acute myeloid leukemias. Leukemia. 2013;27:1401–3.PubMed

75.

Fernandez-Mercado M, Pellagatti A, Di Genua C, Larrayoz MJ, Winkelmann N, Aranaz P, et al. Mutations in SETBP1 are recurrent in myelodysplastic syndromes and often coexist with cytogenetic markers associated with disease progression. Br J Haematol. 2013;163:235–9.PubMed

76.

Laborde RR, Patnaik MM, Lasho TL, Finke CM, Hanson CA, Knudson RA, et al. SETBP1 mutations in 415 patients with primary myelofibrosis or chronic myelomonocytic leukemia: independent prognostic impact in CMML. Leukemia. 2013;27:2100–2.PubMedCentralPubMed

77.

Sakaguchi H, Okuno Y, Muramatsu H, Yoshida K, Shiraishi Y, Takahashi M, et al. Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nat Genet. 2013;45:937–41.PubMed

78.

Shiba N, Ohki K, Park MJ, Sotomatsu M, Kudo K, Ito E, et al. SETBP1 mutations in juvenile myelomonocytic leukaemia and myelodysplastic syndrome but not in paediatric acute myeloid leukaemia. Br J Haematol. 2014;164:156–9.PubMed

79.

Hoischen A, van Bon BW, Gilissen C, Arts P, van Lier B, Steehouwer M, et al. De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. Nat Genet. 2010;42:483–5.PubMed

80.

Cristobal I, Garcia-Orti L, Cirauqui C, Alonso MM, Calasanz MJ, Odero MD. PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect. Leukemia. 2011;25:606–14.PubMed

81.

Panagopoulos I, Kerndrup G, Carlsen N, Strombeck B, Isaksson M, Johansson B. Fusion of NUP98 and the SET binding protein 1 (SETBP1) gene in a paediatric acute T cell lymphoblastic leukaemia with t(11;18)(p15;q12). Br J Haematol. 2007;136:294–6.PubMed

82.

Cristobal I, Blanco FJ, Garcia-Orti L, Marcotegui N, Vicente C, Rifon J, et al. SETBP1 overexpression is a novel leukemogenic mechanism that predicts adverse outcome in elderly patients with acute myeloid leukemia. Blood. 2010;115:615–25.PubMed

83.

Minakuchi M, Kakazu N, Gorrin-Rivas MJ, Abe T, Copeland TD, Ueda K, Adachi Y. Identification and characterization of SEB, a novel protein that binds to the acute undifferentiated leukemia-associated protein SET. Eur J Biochem. 2001;268:1340–51.PubMed

84.

Makishima H, Yoshida K, Nguyen N, Przychodzen B, Sanada M, Okuno Y, et al. Somatic SETBP1 mutations in myeloid malignancies. Nat Genet. 2013;45:942–6.PubMedCentralPubMed

85.

Oakley K, Han Y, Vishwakarma BA, Chu S, Bhatia R, Gudmundsson KO, et al. Setbp1 promotes the self-renewal of murine myeloid progenitors via activation of Hoxa9 and Hoxa10. Blood. 2012;119:6099–108.PubMedCentralPubMed

86.

Klinakis A, Lobry C, Abdel-Wahab O, Oh P, Haeno H, Buonamici S, et al. A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Nature. 2011;473:230–3.PubMedCentralPubMed

87.

Barford D, Neel BG. Revealing mechanisms for SH2 domain mediated regulation of the protein tyrosine phosphatase SHP-2. Structure. 1998;6:249–54.PubMed

88.

Neel BG, Gu H, Pao L. The ‘Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci. 2003;28:284–93.PubMed

89.

Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002;70:1555–63.PubMedCentralPubMed

90.

Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001;29:465–8.PubMed

91.

Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003;34:148–50.PubMed

92.

Gelsi-Boyer V, Trouplin V, Adelaide J, Aceto N, Remy V, Pinson S, et al. Genome profiling of chronic myelomonocytic leukemia: frequent alterations of RAS and RUNX1 genes. BMC Cancer. 2008;8:299.PubMedCentralPubMed

93.

Loh ML, Martinelli S, Cordeddu V, Reynolds MG, Vattikuti S, Lee CM, et al. Acquired PTPN11 mutations occur rarely in adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. Leuk Res. 2005;29:459–62.PubMed

94.

Niemeyer CM, Arico M, Basso G, Biondi A, Cantu Rajnoldi A, Creutzig U, et al. Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS). Blood. 1997;89:3534–43.PubMed

95.

Side LE, Emanuel PD, Taylor B, Franklin J, Thompson P, Castleberry RP, et al. Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1. Blood. 1998;92:267–72.PubMed

96.

Bollag G, Clapp DW, Shih S, Adler F, Zhang YY, Thompson P, et al. Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells. Nat Genet. 1996;12:144–8.PubMed

97.

Haferlach C, Grossmann V, Kohlmann A, Schindela S, Kern W, Schnittger S, et al. Deletion of the tumor-suppressor gene NF1 occurs in 5% of myeloid malignancies and is accompanied by a mutation in the remaining allele in half of the cases. Leukemia. 2012;26:834–9.PubMed

98.

Papaemmanuil E, Cazzola M, Boultwood J, Malcovati L, Vyas P, Bowen D, et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med. 2011;365:1384–95.PubMedCentralPubMed

99.

Grosso AR, Martins S, Carmo-Fonseca M. The emerging role of splicing factors in cancer. EMBO Rep. 2008;9:1087–93.PubMedCentralPubMed

100.

Chen HC, Cheng SC. Functional roles of protein splicing factors. Biosci Rep. 2012;32:345–59.PubMedCentralPubMed

101.

Will CL, Luhrmann R. Spliceosome structure and function. Cold Spring Harb Perspect Biol. 2011;. doi:10.1101/cshperspect.a003707.PubMedCentralPubMed

102.

Scott LM, Rebel VI. Acquired mutations that affect pre-mRNA splicing in hematologic malignancies and solid tumors. J Natl Cancer Inst. 2013;105:1540–9.PubMed

103.

Wahl MC, Will CL, Luhrmann R. The spliceosome: design principles of a dynamic RNP machine. Cell. 2009;136:701–18.PubMed

104.

Kar SA, Jankowska A, Makishima H, Visconte V, Jerez A, Sugimoto Y, et al. Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia. Haematologica. 2013;98:107–13.PubMedCentralPubMed

105.

Makishima H, Visconte V, Sakaguchi H, Jankowska AM, Abu Kar S, Jerez A, et al. Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood. 2012;119:3203–10.PubMedCentralPubMed

106.

Meggendorfer M, Roller A, Haferlach T, Eder C, Dicker F, Grossmann V, et al. SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia (CMML). Blood. 2012;120:3080–8.PubMedCentralPubMed

107.

Przychodzen B, Jerez A, Guinta K, Sekeres MA, Padgett R, Maciejewski JP, et al. Patterns of missplicing due to somatic U2AF1 mutations in myeloid neoplasms. Blood. 2013;122:999–1006.PubMedCentralPubMed

108.

Malcovati L, Papaemmanuil E, Ambaglio I, Elena C, Galli A, Della Porta MG, et al. Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia. Blood. 2014;124(9):1513–21.PubMedCentralPubMed

109.

Graubert TA, Shen D, Ding L, Okeyo-Owuor T, Lunn CL, Shao J, et al. Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat Genet. 2012;44:53–7.

110.

Visconte V, Makishima H, Jankowska A, Szpurka H, Traina F, Jerez A, et al. SF3B1, a splicing factor is frequently mutated in refractory anemia with ring sideroblasts. Leukemia. 2012;26:542–5.PubMed

111.

Visconte V, Rogers HJ, Singh J, Barnard J, Bupathi M, Traina F, et al. SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes. Blood. 2012;120:3173–86.PubMedCentralPubMed

112.

Visconte V, Avishai N, Mahfouz R, Tabarroki A, Cowen J, Sharghi-Moshtaghin R, et al. Distinct iron architecture in SF3B1-mutant myelodysplastic syndrome patients is linked to an SLC25A37 splice variant with a retained intron. Leukemia. 2014;. doi:10.1038/leu.2014.170.

113.

Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122:3616–27 (quiz 3699).PubMedCentralPubMed

114.

Brooks AN, Choi PS, de Waal L, Sharifnia T, Imielinski M, Saksena G, et al. A pan-cancer analysis of transcriptome changes associated with somatic mutations in U2AF1 reveals commonly altered splicing events. PLoS One. 2014;9:e87361.PubMedCentralPubMed

115.

Xiao R, Sun Y, Ding JH, Lin S, Rose DW, Rosenfeld MG, et al. Splicing regulator SC35 is essential for genomic stability and cell proliferation during mammalian organogenesis. Mol Cell Biol. 2007;27:5393–402.PubMedCentralPubMed

116.

Alexander R, Beggs JD. Cross-talk in transcription, splicing and chromatin: who makes the first call? Biochem Soc Trans. 2010;38:1251–6.PubMed

117.

Ernst T, Chase A, Zoi K, Waghorn K, Hidalgo-Curtis C, Score J, et al. Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms. Haematologica. 2010;95:1473–80.PubMedCentralPubMed

118.

Kuo MC, Liang DC, Huang CF, Shih YS, Wu JH, Lin TL, et al. RUNX1 mutations are frequent in chronic myelomonocytic leukemia and mutations at the C-terminal region might predict acute myeloid leukemia transformation. Leukemia. 2009;23:1426–31.PubMed

119.

Blyth K, Cameron ER, Neil JC. The RUNX genes: gain or loss of function in cancer. Nat Rev Cancer. 2005;5:376–87.PubMed

120.

Osato M, Asou N, Abdalla E, Hoshino K, Yamasaki H, Okubo T, et al. Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2alphaB gene associated with myeloblastic leukemias. Blood. 1999;93:1817–24.PubMed

121.

Preudhomme C, Warot-Loze D, Roumier C, Grardel-Duflos N, Garand R, Lai JL, et al. High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21. Blood. 2000;96:2862–9.PubMed

122.

Harada H, Harada Y, Niimi H, Kyo T, Kimura A, Inaba T. High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia. Blood. 2004;103:2316–24.PubMed

123.

Christiansen DH, Andersen MK, Pedersen-Bjergaard J. Mutations of AML1 are common in therapy-related myelodysplasia following therapy with alkylating agents and are significantly associated with deletion or loss of chromosome arm 7q and with subsequent leukemic transformation. Blood. 2004;104:1474–81.PubMed

124.

Harada H, Harada Y, Tanaka H, Kimura A, Inaba T. Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia. Blood. 2003;101:673–80.PubMed

125.

Shih LY, Huang CF, Lin TL, Wu JH, Wang PN, Dunn P, et al. Heterogeneous patterns of CEBPalpha mutation status in the progression of myelodysplastic syndrome and chronic myelomonocytic leukemia to acute myelogenous leukemia. Clin Cancer Res. 2005;11:1821–6.PubMed

126.

Koschmieder S, Halmos B, Levantini E, Tenen DG. Dysregulation of the C/EBPalpha differentiation pathway in human cancer. J Clin Oncol. 2009;27:619–28.PubMedCentralPubMed

127.

Frohling S, Schlenk RF, Stolze I, Bihlmayr J, Benner A, Kreitmeier S, et al. CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J Clin Oncol. 2004;22:624–33.PubMed

128.

Leroy H, Roumier C, Huyghe P, Biggio V, Fenaux P, Preudhomme C. CEBPA point mutations in hematological malignancies. Leukemia. 2005;19:329–34.PubMed

129.

Smith ML, Cavenagh JD, Lister TA, Fitzgibbon J. Mutation of CEBPA in familial acute myeloid leukemia. N Engl J Med. 2004;351:2403–7.PubMed

130.

Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352:254–66.PubMed

131.

Grisendi S, Mecucci C, Falini B, Pandolfi PP. Nucleophosmin and cancer. Nat Rev Cancer. 2006;6:493–505.PubMed

132.

Padua RA, Guinn BA, Al-Sabah AI, Smith M, Taylor C, Pettersson T, et al. RAS, FMS and p53 mutations and poor clinical outcome in myelodysplasias: a 10-year follow-up. Leukemia. 1998;12:887–92.PubMed

133.

Harutyunyan A, Klampfl T, Cazzola M, Kralovics R. p53 lesions in leukemic transformation. N Engl J Med. 2011;364:488–90.PubMed

134.

Cazzola M. Della Porta MG, Malcovati L. The genetic basis of myelodysplasia and its clinical relevance. Blood. 2013;122:4021–34.PubMedCentralPubMed

135.

Sugimoto K, Hirano N, Toyoshima H, Chiba S, Mano H, Takaku F, et al. Mutations of the p53 gene in myelodysplastic syndrome (MDS) and MDS-derived leukemia. Blood. 1993;81:3022–6.PubMed

136.

Kanagal-Shamanna R, Bueso-Ramos CE, Barkoh B, Lu G, Wang S, Garcia-Manero G, et al. Myeloid neoplasms with isolated isochromosome 17q represent a clinicopathologic entity associated with myelodysplastic/myeloproliferative features, a high risk of leukemic transformation, and wild-type TP53. Cancer. 2012;118:2879–88.PubMed

137.

Thota S, Viny AD, Makishima H, Spitzer B, Radivoyevitch T, Przychodzen B, et al. Genetic alterations of the cohesin complex genes in myeloid malignancies. Blood. 2014. doi:10.1182/blood-2014-04-567057.

138.

Gruber S, Haering CH, Nasmyth K. Chromosomal cohesin forms a ring. Cell. 2003;112:765–77.PubMed

139.

Nasmyth K, Haering CH. Cohesin: its roles and mechanisms. Annu Rev Genet. 2009;43:525–58.PubMed

140.

Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349:2042–54.PubMed

141.

Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18:553–67.PubMedCentralPubMed

142.

Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. 2011;333:1300–3.PubMedCentralPubMed

143.

Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324:930–5.PubMedCentralPubMed

144.

Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood. 2009;114:144–7.PubMedCentralPubMed

145.

Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360:2289–301.PubMed

146.

Jankowska AM, Szpurka H, Tiu RV, Makishima H, Afable M, Huh J, et al. Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood. 2009;113:6403–10.PubMedCentralPubMed

147.

Kosmider O, Gelsi-Boyer V, Cheok M, Grabar S, Della-Valle V, Picard F, et al. TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs). Blood. 2009;114:3285–91.PubMed

148.

Kosmider O, Gelsi-Boyer V, Ciudad M, Racoeur C, Jooste V, Vey N, et al. TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leukemia. Haematologica. 2009;94:1676–81.PubMedCentralPubMed

149.

Reiter A, Invernizzi R, Cross NC, Cazzola M. Molecular basis of myelodysplastic/myeloproliferative neoplasms. Haematologica. 2009;94:1634–8.PubMedCentralPubMed

150.

Tefferi A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Patnaik MM, et al. Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms: CMML, MDS, MDS/MPN and AML. Leukemia. 2009;23:1343–5.PubMed

151.

Abdel-Wahab O, Pardanani A, Rampal R, Lasho TL, Levine RL, Tefferi A. DNMT3A mutational analysis in primary myelofibrosis, chronic myelomonocytic leukemia and advanced phases of myeloproliferative neoplasms. Leukemia. 2011;25:1219–20.PubMed

152.

Fernandez-Mercado M, Yip BH, Pellagatti A, Davies C, Larrayoz MJ, Kondo T, et al. Mutation patterns of 16 genes in primary and secondary acute myeloid leukemia (AML) with normal cytogenetics. PLoS One. 2012;7:e42334.PubMedCentralPubMed

153.

Jankowska AM, Makishima H, Tiu RV, Szpurka H, Huang Y, Traina F, et al. Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A. Blood. 2011;118:3932–41.PubMedCentralPubMed

154.

Carbuccia N, Murati A, Trouplin V, Brecqueville M, Adelaide J, Rey J, et al. Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia. 2009;23:2183–6.PubMed

155.

Abdel-Wahab O, Adli M, LaFave LM, Gao J, Hricik T, Shih AH, et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell. 2012;22:180–93.PubMedCentralPubMed

156.

Itzykson R, Kosmider O, Fenaux P. Somatic mutations and epigenetic abnormalities in myelodysplastic syndromes. Best Pract Res Clin Haematol. 2013;26:355–64.PubMed

157.

Patnaik MM, Itzykson R, Lasho TL, Kosmider O, Finke CM, Hanson CA, et al. ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients. Leukemia. 2014;. doi:10.1038/leu.2014.125.

158.

Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011;364:2496–506.PubMedCentralPubMed

159.

Such E, Germing U, Malcovati L, Cervera J, Kuendgen A, Della Porta MG, et al. Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia. Blood. 2013;121:3005–15.PubMed

160.

Guglielmelli P, Lasho TL, Rotunno G, Score J, Mannarelli C, Pancrazzi A, et al. The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia. 2014;28(9):1804–10.PubMed

Titel: Molecular pathogenesis of atypical CML, CMML and MDS/MPN-unclassifiable
verfasst von: Katerina Zoi
Nicholas C. P. Cross
Publikationsdatum: 01.03.2015
Verlag: Springer Japan
Erschienen in: International Journal of Hematology / Ausgabe 3/2015
Print ISSN: 0925-5710
Elektronische ISSN: 1865-3774
DOI: https://doi.org/10.1007/s12185-014-1670-3

Neu im Fachgebiet Onkologie

24.04.2024 | DGIM 2024 | Nachrichten

Springer Medizin

Molecular pathogenesis of atypical CML, CMML and MDS/MPN-unclassifiable

Abstract

Neu im Fachgebiet Onkologie

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Update Onkologie

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 3/2015

Phase 1 study in Japan of siltuximab, an anti-IL-6 monoclonal antibody, in relapsed/refractory multiple myeloma

The Effect of Preoperative Vitamin K on the INR in Bridging Therapy

Allogeneic hematopoietic cell transplantation for acute myeloid leukemia during first complete remission: a clinical perspective

Donald Metcalf, ‘Father of CSF’ (1929–2014)

Treatment patterns and clinical outcomes in patients with chronic immune thrombocytopenia (ITP) switched to eltrombopag or romiplostim

Significance of lymphocyte counts at diagnosis in the management of ITP: the relationship between lymphocyte counts and treatment success in H. pylori-infected patients

Neu im Fachgebiet Onkologie

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Update Onkologie