The molecular basis and clinical significance of genetic mutations identified in myelodysplastic syndromes

Leukemia Research - Tập 39 - Trang 6-17 - 2015
Ling Zhang1, Eric Padron2, Jeffrey Lancet2
1Department of Hematopathology and Laboratory Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
2Department of Hematologic Malignancies, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States

Tài liệu tham khảo

Brunning, 2008, 88 Bejar, 2011, Unraveling the molecular pathophysiology of myelodysplastic syndromes, J Clin Oncol, 29, 504, 10.1200/JCO.2010.31.1175 Bejar, 2011, Clinical effect of point mutations in myelodysplastic syndromes, N Engl J Med, 30, 2496, 10.1056/NEJMoa1013343 Bejar, 2013, Prognostic models in myelodysplastic syndromes, Hematology Am Soc Hematol Educ Program, 2013, 504, 10.1182/asheducation-2013.1.504 Marshall, 2013, Standardizing the initial evaluation for myelodysplastic syndromes, Curr Hematol Malig Rep, 8, 361, 10.1007/s11899-013-0180-3 Cazzola, 2013, The genetic basis of myelodysplasia and its clinical relevance, Blood, 122, 4021, 10.1182/blood-2013-09-381665 Haferlach, 2014, Landscape of genetic lesions in 944 patients with myelodysplastic syndromes, Leukemia, 28, 241, 10.1038/leu.2013.336 Papaemmanuil, 2013, Clinical and biological implications of driver mutations in myelodysplastic syndromes, Blood, 122, 3616, 10.1182/blood-2013-08-518886 Kulasekararaj, 2013, Recent advances in understanding the molecular pathogenesis of myelodysplastic syndromes, Br J Haematol, 162, 587, 10.1111/bjh.12435 Bestor, 2000, The DNA methyltransferases of mammals, Hum Mol Genet, 9, 2395, 10.1093/hmg/9.16.2395 Li, 2013, DNA methyltransferases in hematologic malignancies, Semin Hematol, 50, 48, 10.1053/j.seminhematol.2013.01.005 Tahiliani, 2009, Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1, Science, 324, 930, 10.1126/science.1170116 Kriaucionis, 2009, The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain, Science, 324, 929, 10.1126/science.1169786 Bhutani, 2011, DNA demethylation dynamics, Cell, 146, 866, 10.1016/j.cell.2011.08.042 Song, 2012, Balance of DNA methylation and demethylation in cancer development, Genome Biol, 13, 173, 10.1186/gb-2012-13-10-2012 Delhommeau, 2009, Mutation in TET2 in myeloid cancers, N Engl J Med, 360, 2289, 10.1056/NEJMoa0810069 Jankowska, 2009, Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms, Blood, 113, 6403, 10.1182/blood-2009-02-205690 Itzykson, 2013, Prognostic score including gene mutations in chronic myelomonocytic leukemia, J Clin Oncol, 31, 2428, 10.1200/JCO.2012.47.3314 Kosmider, 2009, TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leukemia, Haematologica, 94, 1676, 10.3324/haematol.2009.011205 Graubert, 2011, Genetics of myelodysplastic syndromes: new insights, Hematology Am Soc Hematol Educ Program, 2011, 543, 10.1182/asheducation-2011.1.543 Lindsley, 2013, Molecular pathophysiology of myelodysplastic syndromes, Annu Rev Pathol, 8, 21, 10.1146/annurev-pathol-011811-132436 Moran-Crusio, 2011, Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation, Cancer Cell, 20, 11, 10.1016/j.ccr.2011.06.001 Ko, 2010, Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2, Nature, 468, 839, 10.1038/nature09586 Ko, 2011, Ten-eleven-translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice, Proc Natl Acad Sci U S A, 108, 14566, 10.1073/pnas.1112317108 Quivoron, 2011, TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis, Cancer Cell, 20, 25, 10.1016/j.ccr.2011.06.003 Abdel-Wahab, 2011, Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms, Leukemia, 25, 1200, 10.1038/leu.2011.58 Figueroa, 2010, Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation, Cancer Cell, 18, 553, 10.1016/j.ccr.2010.11.015 Muto, 2013, Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders, J Exp Med, 210, 2627, 10.1084/jem.20131144 Shide, 2012, TET2 is essential for survival and hematopoietic stem cell homeostasis, Leukemia, 26, 2216, 10.1038/leu.2012.94 Bejar, 2012, Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes, J Clin Oncol, 30, 3376, 10.1200/JCO.2011.40.7379 Itzykson, 2011, Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias, Leukemia, 25, 1147, 10.1038/leu.2011.71 Sekeres, 2012, Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes, Blood, 120, 4945, 10.1182/blood-2012-06-434639 Traina, 2014, Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms, Leukemia, 28, 78, 10.1038/leu.2013.269 Liu, 2013, Decreased 5-hydroxymethylcytosine levels are associated with TET2 mutation and unfavorable overall survival in myelodysplastic syndromes, Leuk Lymphoma, 54, 2466, 10.3109/10428194.2013.778408 Goll, 2005, Eukaryotic cytosine methyltransferases, Annu Rev Biochem, 74, 481, 10.1146/annurev.biochem.74.010904.153721 Tsujioka, 2013, Effects of DNA methyltransferase inhibitors (DNMTIs) on MDS-derived cell lines, Exp Hematol, 41, 189, 10.1016/j.exphem.2012.10.006 Xu, 1999, Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene, Nature, 402, 187, 10.1038/46214 Ley, 2010, DNMT3A mutations in acute myeloid leukemia, N Engl J Med, 363, 2424, 10.1056/NEJMoa1005143 Thol, 2011, Rare occurrence of DNMT3A mutations in myelodysplastic syndromes, Haematologica, 96, 1870, 10.3324/haematol.2011.045559 Walter, 2011, Recurrent DNMT3A mutations in patients with myelodysplastic syndromes, Leukemia, 25, 1153, 10.1038/leu.2011.44 Kolquist, 2011, Microarray-based comparative genomic hybridization of cancer targets reveals novel, recurrent genetic aberrations in the myelodysplastic syndromes, Cancer Genet, 204, 603, 10.1016/j.cancergen.2011.10.004 Xu, 2004, Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity, J Biol Chem, 279, 33946, 10.1074/jbc.M404298200 Fathi, 2012, Mutations in epigenetic modifiers in myeloid malignancies and the prospect of novel epigenetic-targeted therapy, Adv Hematol, 2012, 469592, 10.1155/2012/469592 Losman, 2013, What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer, Genes Dev, 27, 836, 10.1101/gad.217406.113 Parsons, 2008, An integrated genomic analysis of human glioblastoma multiforme, Science, 321, 1807, 10.1126/science.1164382 Patnaik, 2012, Differential prognostic effect of IDH1 versus IDH2 mutations in myelodysplastic syndromes: a Mayo clinic study of 277 patients, Leukemia, 26, 101, 10.1038/leu.2011.298 Tefferi, 2010, DH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis, Leukemia, 24, 1302, 10.1038/leu.2010.113 Thol, 2010, IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis, Haematologica, 95, 1668, 10.3324/haematol.2010.025494 Soverini, 2012, IDH2 somatic mutations in chronic myeloid leukemia patients in blast crisis, Leukemia, 25, 178, 10.1038/leu.2010.236 Boissel, 2010, Prognostic impact of isocitrate dehydrogenase enzyme isoforms 1 and 2 mutations in acute myeloid leukemia: a study by the Acute Leukemia French Association group, J Clin Oncol, 28, 3717, 10.1200/JCO.2010.28.2285 Chowdhury, 2011, The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases, EMBO Rep, 12, 463, 10.1038/embor.2011.43 Rakheja, 2013, The emerging role of d-2-hydroxyglutarate as an oncometabolite in hematolymphoid and central nervous system neoplasms, Front Oncol, 3, 169, 10.3389/fonc.2013.00169 Xu, 2011, Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases, Cancer Cell, 19, 17, 10.1016/j.ccr.2010.12.014 Lin, 2014, IDH mutations are closely associated with mutations of DNMT3A, ASXL1 and SRSF2 in patients with myelodysplastic syndromes and are stable during disease evolution, Am J Hematol, 89, 137, 10.1002/ajh.23596 Patnaik, 2010, WHO-defined ‘myelodysplastic syndrome with isolated del(5q)’ in 88 consecutive patients: survival data, leukemic transformation rates and prevalence of JAK2, MPL and IDH mutations, Leukemia, 24, 1283, 10.1038/leu.2010.105 Krell, 2013, IDH mutations in tumorigenesis and their potential role as novel therapeutic targets, Future Oncol, 9, 1923, 10.2217/fon.13.143 Abdel-Wahab, 2012, Interpreting new molecular genetics in myelodysplastic syndromes, Hematology Am Soc Hematol Educ Program, 2012, 56, 10.1182/asheducation.V2012.1.56.3798194 Kamminga, 2006, The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion, Blood, 107, 2170, 10.1182/blood-2005-09-3585 Lee, 2006, Control of developmental regulators by Polycomb in human embryonic stem cells, Cell, 125, 301, 10.1016/j.cell.2006.02.043 Margueron, 2011, The polycomb complex PRC2 and its mark in life, Nature, 469, 343, 10.1038/nature09784 Boyer, 2006, Polycomb complexes repress developmental regulators in murine embryonic stem cells, Nature, 441, 349, 10.1038/nature04733 Kondo, 2008, Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation, Nat Genet, 40, 741, 10.1038/ng.159 Gelsi-Boyer, 2009, Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia, Br J Haematol, 145, 788, 10.1111/j.1365-2141.2009.07697.x Abdel-Wahab, 2012, ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression, Cancer Cell, 22, 180, 10.1016/j.ccr.2012.06.032 Wang, 2013, TET2, ASXL1 and EZH2 mutations in Chinese with myelodysplastic syndromes, Leuk Res, 37, 305, 10.1016/j.leukres.2012.10.004 Wang, 2014, Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice, Blood, 123, 541, 10.1182/blood-2013-05-500272 Dey, 2012, Loss of the tumor suppressor BAP1 causes myeloid transformation, Science, 337, 1541, 10.1126/science.1221711 Szpurka, 2010, Spectrum of mutations in RARS-T patients includes TET2 and ASXL1 mutations, Leuk Res, 34, 969, 10.1016/j.leukres.2010.02.033 Gelsi-Boyer, 2010, ASXL1 mutation is associated with poor prognosis and acute transformation in chronic myelomonocytic leukaemia, Br J Haematol, 151, 365, 10.1111/j.1365-2141.2010.08381.x Bacher, 2014, Investigation of 305 patients with myelodysplastic syndromes and 20q deletion for associated cytogenetic and molecular genetic lesions and their prognostic impact, Br J Haematol, 164, 822, 10.1111/bjh.12710 Morin, 2010, Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin, Nat Genet, 42, 181, 10.1038/ng.518 Ernst, 2010, Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders, Nat Genet, 42, 722, 10.1038/ng.621 Guglielmelli, 2011, EZH2 mutational status predicts poor survival in myelofibrosis, Blood, 118, 5227, 10.1182/blood-2011-06-363424 Grossmann, 2011, Molecular profiling of chronic myelomonocytic leukemia reveals diverse mutations in >80% of patients with TET2 and EZH2 being of high prognostic relevance, Leukemia, 25, 877, 10.1038/leu.2011.10 Agger, 2007, UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development, Nature, 449, 731, 10.1038/nature06145 Thieme, 2013, The histone demethylase UTX regulates stem cell migration and hematopoiesis, Blood, 121, 2462, 10.1182/blood-2012-08-452003 Jankowska, 2012, Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A, Blood, 118, 3932, 10.1182/blood-2010-10-311019 van Haaften, 2009, Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer, Nat Genet, 41, 521, 10.1038/ng.349 Song, 1999, Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia, Nat Genet, 23, 166, 10.1038/13793 Imai, 2000, Mutations of the AML1 gene in myelodysplastic syndrome and their functional implications in leukemogenesis, Blood, 96, 3154, 10.1182/blood.V96.9.3154 Harada, 2004, High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia, Blood, 103, 2316, 10.1182/blood-2003-09-3074 Kuo, 2009, RUNX1 mutations are frequent in chronic myelomonocytic leukemia and mutation s at the C-terminal region might predict acute myeloid leukemia transformation, Leukemia, 23, 1426, 10.1038/leu.2009.48 Steensma, 2005, Somatic point mutations in RUNX1/CBFA2/AML1 are common in high-risk myelodysplastic syndrome, but not in myelofibrosis with myeloid metaplasia, Eur J Haematol, 74, 47, 10.1111/j.1600-0609.2004.00363.x Dicker, 2010, Mutation analysis for RUNX1, MLL-PTD, FLT3-ITD, NPM1 and NRAS in 269 patients with MDS or secondary AML, Leukemia, 24, 1528, 10.1038/leu.2010.124 Chen, 2007, RUNX1 gene mutation in primary myelodysplastic syndrome – the mutation can be detected early at diagnosis or acquired during disease progression and is associated with poor outcome, Br J Haematol, 139, 405, 10.1111/j.1365-2141.2007.06811.x Huynh, 2000, BCoR, a novel corepressor involved in BCL-6 repression, Genes Dev, 14, 1810, 10.1101/gad.14.14.1810 Li, 2011, Somatic mutations in the transcriptional corepressor gene BCORL1 in adult acute myelogenous leukemia, Blood, 118, 5914, 10.1182/blood-2011-05-356204 Pagan, 2007, A novel corepressor, BCoR-L1, represses transcription through an interaction with CtBP, J Biol Chem, 282, 15248, 10.1074/jbc.M700246200 Wamstad, 2008, Role of the transcriptional corepressor BCOR in embryonic stem cell differentiation and early embryonic development, PLoS ONE, 3, e2814, 10.1371/journal.pone.0002814 Damm, 2013, BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders, Blood, 2122, 3169, 10.1182/blood-2012-11-469619 Grossmann, 2011, Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype, Blood, 118, 6153, 10.1182/blood-2011-07-365320 Golub, 1994, Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation, Cell, 77, 307, 10.1016/0092-8674(94)90322-0 Golub, 1995, Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia, Proc Natl Acad Sci U S A, 92, 4917, 10.1073/pnas.92.11.4917 De Braekeleer, 2012, ETV6 fusion genes in hematological malignancies: a review, Leuk Res, 36, 945, 10.1016/j.leukres.2012.04.010 Raynaud, 1996, Fluorescence in situ hybridization analysis of t(3; 12)(q26; p13): a recurring chromosomal abnormality involving the TEL gene (ETV6) in myelodysplastic syndromes, Blood, 15, 682, 10.1182/blood.V88.2.682.bloodjournal882682 Haferlach, 2012, ETV6 rearrangements are recurrent in myeloid malignancies and are frequently associated with other genetic events, Genes Chromosomes Cancer, 51, 328, 10.1002/gcc.21918 Montano-Almendras, 2012, ETV6-PDGFRB and FIP1L1-PDGFRA stimulate human hematopoietic progenitor cell proliferation and differentiation into eosinophils: the role of nuclear factor-κB, Haematologica, 97, 1064, 10.3324/haematol.2011.047530 Walz, 2011, Response of ETV6-FLT3-positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3, Blood, 118, 2239, 10.1182/blood-2011-03-343426 Barjesteh van Waalwijk van Doorn-Khosrovani, 2005, Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia, Oncogene, 24, 4129, 10.1038/sj.onc.1208588 Silva, 2008, ETV6 mutations and loss in AML-M0, Leukemia, 22, 1639, 10.1038/leu.2008.34 Wall, 2012, ETV6 deletion is a common additional abnormality in patients with myelodysplastic syndromes or acute myeloid leukemia and monosomy 7, Haematologica, 97, 1933, 10.3324/haematol.2012.069716 Padron, 2014, ETV6 and signaling gene mutations are associated with secondary transformation of myelodysplastic syndromes to chronic myelomonocytic leukemia, Blood, 123, 3675, 10.1182/blood-2014-03-562637 Cristobal, 2010, SETBP1 overexpression is a novel leukemogenic mechanism that predicts adverse outcome in elderly patients with acute myeloid leukemia, Blood, 115, 615, 10.1182/blood-2009-06-227363 Hoischen, 2010, De novo mutations of SETBP1 cause Schinzel–Giedion syndrome, Nat Genet, 42, 483, 10.1038/ng.581 Piazza, 2013, Recurrent SETBP1 mutations in atypical chronic myeloid leukemia, Nat Genet, 45, 18, 10.1038/ng.2495 Hou, 2014, Clinical implications of the SETBP1 mutation in patients with primary myelodysplastic syndrome and its stability during disease progression, Am J Hematol, 89, 181, 10.1002/ajh.23611 Fernandez-Mercado, 2013, Mutations in SETBP1 are recurrent in myelodysplastic syndromes and often coexist with cytogenetic markers associated with disease progression, Br J Haematol, 163, 235 Damm, 2013, SETBP1 mutations in 658 patients with myelodysplastic syndromes, chronic myelomonocytic leukemia and secondary acute myeloid leukemias, Leukemia, 27, 1401, 10.1038/leu.2013.35 Makishima, 2013, Somatic SETBP1 mutations in myeloid malignancies, Nat Genet, 45, 942, 10.1038/ng.2696 Hahn, 2011, Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia, Nat Genet, 43, 1012, 10.1038/ng.913 Hyde, 2011, GATA2 mutations lead to MDS and AML, Nat Genet, 43, 926, 10.1038/ng.949 Ostergaard, 2011, Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome), Nat Genet, 43, 929, 10.1038/ng.923 Dickinson, 2011, Exome sequencing identifies GATA2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency, Blood, 118, 2656, 10.1182/blood-2011-06-360313 Hsu, 2011, Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome, Blood, 118, 2653, 10.1182/blood-2011-05-356352 Dickinson, 2014, The evolution of cellular deficiency in GATA2 mutation, Blood, 123, 863, 10.1182/blood-2013-07-517151 Pasquet, 2013, High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia, Blood, 121, 822, 10.1182/blood-2012-08-447367 Petitjean, 2007, TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes, Oncogene, 26, 2157, 10.1038/sj.onc.1210302 Sugimoto, 1993, Mutations of the p53 gene in myelodysplastic syndrome (MDS) and MDS-derived leukemia, Blood, 81, 3022, 10.1182/blood.V81.11.3022.3022 Kulasekararaj, 2013, TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis, Br J Haematol, 160, 660, 10.1111/bjh.12203 Jädersten, 2011, TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression, J Clin Oncol, 29, 1971, 10.1200/JCO.2010.31.8576 Caceres, 2013, TP53 suppression promotes erythropoiesis in del(5q) MDS, suggesting a targeted therapeutic strategy in lenalidomide-resistant patients, Proc Natl Acad Sci U S A, 110, 16127, 10.1073/pnas.1311055110 Levine, 2005, Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis, Cancer Cell, 7, 387, 10.1016/j.ccr.2005.03.023 Steensma, 2005, The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes, Blood, 106, 1207, 10.1182/blood-2005-03-1183 Ingram, 2006, The JAK2 V617F mutation identifies a subgroup of MDS patients with isolated deletion 5q and a proliferative bone marrow, Leukemia, 20, 1319, 10.1038/sj.leu.2404215 De Renzis, 2013, Prognostic impact of JAK2V617F mutation in myelodysplatic syndromes: a matched case–control study, Leuk Res Rep, 2, 64 Nadeau, 2012, Oncogenic signaling by leukemia-associated mutant Cbl proteins, Biochem Anal Biochem Suppl, 6, 7921 Sanada, 2009, Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms, Nature, 1460, 904, 10.1038/nature08240 Rathinam, 2008, The E3 ubiquitin ligase c-Cbl restricts development and functions of hematopoietic stem cells, Genes Dev, 22, 992, 10.1101/gad.1651408 Bunda, 2014, Juvenile myelomonocytic leukaemia-associated mutation in Cbl promotes resistance to apoptosis via the Lyn-PI3K/AKT pathway, Oncogene Kohlmann, 2010, 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, 28, 3858, 10.1200/JCO.2009.27.1361 Schwaab, 2012, Activating CBL mutations are associated with a distinct MDS/MPN phenotype, Ann Hematol, 91, 1713, 10.1007/s00277-012-1521-3 Kao, 2011, A high occurrence of acquisition and/or expansion of C-CBL mutant clones in the progression of high-risk myelodysplastic syndrome to acute myeloid leukemia, Neoplasia, 13, 1035, 10.1593/neo.111192 Hancock, 2003, Ras proteins: different signals from different locations, Nat Rev Mol Cell Biol, 4, 373, 10.1038/nrm1105 Paquette, 1993, N-ras mutations are associated with poor prognosis and increased risk of leukemia in myelodysplastic syndrome, Blood, 82, 590, 10.1182/blood.V82.2.590.590 Wang, 2010, Endogenous oncogenic Nras mutation promotes aberrant GM-CSF signaling in granulocytic/monocytic precursors in a murine model of chronic myelomonocytic leukemia, Blood, 116, 5991, 10.1182/blood-2010-04-281527 Damm, 2012, Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes, Blood, 119, 3211, 10.1182/blood-2011-12-400994 Boultwood, 2014, The role of splicing factor mutations in the pathogenesis of the myelodysplastic syndromes, Adv Biol Regul, 54C, 153, 10.1016/j.jbior.2013.09.005 Yoshida, 2011, Frequent pathway mutations of splicing machinery in myelodysplasia, Nature, 478, 64, 10.1038/nature10496 Yoshida, 2014, Splicing factor mutations and cancer, Wiley Interdiscip Rev RNA, 5, 445, 10.1002/wrna.1222 Padgett, 2012, New connections between splicing and human disease, Trends Genet, 28, 147, 10.1016/j.tig.2012.01.001 Papaemmanuil, 2011, Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts, N Engl J Med, 365, 1384, 10.1056/NEJMoa1103283 Patnaik, 2012, SF3B1 mutations are prevalent in myelodysplastic syndromes with ring sideroblasts but do not hold independent prognostic value, Blood, 119, 569, 10.1182/blood-2011-09-377994 Makishima, 2012, Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis, Blood, 119, 3203, 10.1182/blood-2011-12-399774 Seo, 2014, Clinical significance of SF3B1 mutations in Korean patients with myelodysplastic syndromes and myelodysplasia/myeloproliferative neoplasms with ring sideroblasts, Ann Hematol, 93, 603, 10.1007/s00277-013-1915-x Ye, 2010, Erythropoiesis and iron sulfur cluster biogenesis, Adv Hematol, 2010, 10.1155/2010/329394 Cazzola, 2013, Biologic and clinical significance of somatic mutations of SF3B1 in myeloid and lymphoid neoplasms, Blood, 121, 260, 10.1182/blood-2012-09-399725 Wu, 2012, The clinical implication of SRSF2 mutation in patients with myelodysplastic syndrome and its stability during disease evolution, Blood, 120, 3106, 10.1182/blood-2012-02-412296 Thol, 2012, Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes, Blood, 119, 3578, 10.1182/blood-2011-12-399337 Graubert, 2011, Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes, Nat Genet, 44, 53, 10.1038/ng.1031 Przychodzen, 2013, Patterns of missplicing due to somatic U2AF1 mutations in myeloid neoplasms, Blood, 8, 999, 10.1182/blood-2013-01-480970 Wu, 2013, Clinical implications of U2AF1 mutation in patients with myelodysplastic syndrome and its stability during disease progression, Am J Hematol, 88, E277, 10.1002/ajh.23541 Barbero, 2009, Cohesins: chromatin architects in chromosome segregation, control of gene expression and much more, Cell Mol Life Sci, 66, 2025, 10.1007/s00018-009-0004-8 Kon, 2013, Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms, Nat Genet, 45, 1232, 10.1038/ng.2731 Walter, 2012, Clonal architecture of secondary acute myeloid leukemia, N Engl J Med, 366, 1090, 10.1056/NEJMoa1106968 Thol, 2014, Mutations in the cohesin complex in acute myeloid leukemia: clinical and prognostic implications, Blood, 123, 914, 10.1182/blood-2013-07-518746 Solomon DA1, 2011, Mutational inactivation of STAG2 causes aneuploidy in human cancer, Science, 333, 1039, 10.1126/science.1203619 Nybakken, 2014, The genetic basis and expanding role of molecular analysis in the diagnosis, prognosis, and therapeutic design for myelodysplastic syndromes, J Mol Diagn, 16, 145, 10.1016/j.jmoldx.2013.11.005 Davids, 2010, The molecular pathogenesis of myelodysplastic syndromes, Cancer Biol Ther, 10, 309, 10.4161/cbt.10.4.12612