Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression

Blood - Tập 118 - Trang 167-176 - 2011
Thorsten Klampfl1, Ashot Harutyunyan1, Tiina Berg1, Bettina Gisslinger2, Martin Schalling1, Klaudia Bagienski1, Damla Olcaydu1, Francesco Passamonti3, Elisa Rumi4, Daniela Pietra4, Roland Jäger1, Lisa Pieri5, Paola Guglielmelli5, Ilaria Iacobucci6, Giovanni Martinelli6, Mario Cazzola4, Alessandro M. Vannucchi5, Heinz Gisslinger2, Robert Kralovics1,2
1Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria;
2Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, Austria;
3Division of Hematology, Azienda Ospedaliera Universitaria Fondazione Macchi, Varese, Italy;
4Department of Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, University of Pavia, Pavia, Italy;
5Section of Hematology, University of Florence, Florence, Italy;
6Department of Hematology and Oncological Sciences L. and A. Seragnoli, University of Bologna, Bologna, Italy

Tóm tắt

Abstract Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) are clonal myeloid disorders with increased production of terminally differentiated cells. The disease course is generally chronic, but some patients show disease progression (secondary myelofibrosis or accelerated phase) and/or leukemic transformation. We investigated chromosomal aberrations in 408 MPN samples using high-resolution single-nucleotide polymorphism microarrays to identify disease-associated somatic lesions. Of 408 samples, 37.5% had a wild-type karyotype and 62.5% harbored at least 1 chromosomal aberration. We identified 25 recurrent aberrations that were found in 3 or more samples. An increased number of chromosomal lesions was significantly associated with patient age, as well as with disease progression and leukemic transformation, but no association was observed with MPN subtypes, Janus kinase 2 (JAK2) mutational status, or disease duration. Aberrations of chromosomes 1q and 9p were positively associated with disease progression to secondary myelofibrosis or accelerated phase. Changes of chromosomes 1q, 7q, 5q, 6p, 7p, 19q, 22q, and 3q were positively associated with post-MPN acute myeloid leukemia. We mapped commonly affected regions to single target genes on chromosomes 3p (forkhead box P1 [FOXP1]), 4q (tet oncogene family member 2 [TET2]), 7p (IKAROS family zinc finger 1 [IKZF1]), 7q (cut-like homeobox 1 [CUX1]), 12p (ets variant 6 [ETV6]), and 21q (runt-related transcription factor 1 [RUNX1]). Our data provide insight into the genetic complexity of MPNs and implicate new genes involved in disease progression.

Tài liệu tham khảo

Campbell, 2006, The myeloproliferative disorders., N Engl J Med, 355, 2452, 10.1056/NEJMra063728 Tam, 2009, Dynamic model for predicting death within 12 months in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis., J Clin Oncol, 27, 5587, 10.1200/JCO.2009.22.8833 Abdulkarim, 2009, AML transformation in 56 patients with Ph- MPD in two well defined populations., Eur J Haematol, 82, 106, 10.1111/j.1600-0609.2008.01163.x Hussein, 2009, Conventional cytogenetics in myelofibrosis: literature review and discussion., Eur J Haematol, 82, 329, 10.1111/j.1600-0609.2009.01224.x Gangat, 2009, Cytogenetic abnormalities in essential thrombocythemia: prevalence and prognostic significance., Eur J Haematol, 83, 17, 10.1111/j.1600-0609.2009.01246.x Panani, 2007, Cytogenetic and molecular aspects of Philadelphia negative chronic myeloproliferative disorders: clinical implications., Cancer Lett, 255, 12, 10.1016/j.canlet.2007.02.009 Gangat, 2008, Cytogenetic studies at diagnosis in polycythemia vera: clinical and JAK2V617F allele burden correlates., Eur J Haematol, 80, 197, 10.1111/j.1600-0609.2007.01003.x Reilly, 2008, Pathogenetic insight and prognostic information from standard and molecular cytogenetic studies in the BCR-ABL-negative myeloproliferative neoplasms (MPNs)., Leukemia, 22, 1818, 10.1038/leu.2008.218 Kralovics, 2002, Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera., Exp Hematol, 30, 229, 10.1016/S0301-472X(01)00789-5 Baxter, 2005, Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders., Lancet, 365, 1054, 10.1016/S0140-6736(05)71142-9 James, 2005, A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera., Nature, 434, 1144, 10.1038/nature03546 Kralovics, 2005, A gain-of-function mutation of JAK2 in myeloproliferative disorders., N Engl J Med, 352, 1779, 10.1056/NEJMoa051113 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 Pardanani, 2006, MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients., Blood, 108, 3472, 10.1182/blood-2006-04-018879 Szpurka, 2009, UPD1p indicates the presence of MPL W515L mutation in RARS-T, a mechanism analogous to UPD9p and JAK2 V617F mutation., Leukemia, 23, 610, 10.1038/leu.2008.249 Buxhofer-Ausch, 2009, Acquired resistance to interferon alpha therapy associated with homozygous MPL-W515L mutation and chromosome 20q deletion in primary myelofibrosis., Eur J Haematol, 82, 161, 10.1111/j.1600-0609.2008.01183.x Delhommeau, 2009, Mutation in TET2 in myeloid cancers., N Engl J Med, 360, 2289, 10.1056/NEJMoa0810069 Tefferi, 2009, TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis., Leukemia, 23, 905, 10.1038/leu.2009.47 Dunbar, 2008, 250K single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c-Cbl, in myeloid malignancies., Cancer Res, 68, 10349, 10.1158/0008-5472.CAN-08-2754 Sanada, 2009, Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms., Nature, 460, 904, 10.1038/nature08240 Carbuccia, 2009, Mutations of ASXL1 gene in myeloproliferative neoplasms., Leukemia, 23, 2183, 10.1038/leu.2009.141 Green, 2010, Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms., N Engl J Med, 362, 369, 10.1056/NEJMc0910063 Jäger, 2010, Deletions of the transcription factor Ikaros in myeloproliferative neoplasms., Leukemia, 24, 1290, 10.1038/leu.2010.99 Thoennissen, 2010, Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosome-negative myeloproliferative neoplasms., Blood, 115, 2882, 10.1182/blood-2009-07-235119 Stegelmann, 2010, High-resolution single-nucleotide polymorphism array-profiling in myeloproliferative neoplasms identifies novel genomic aberrations., Haematologica, 95, 666, 10.3324/haematol.2009.013623 Kralovics, 2006, Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders., Blood, 108, 1377, 10.1182/blood-2005-11-009605 Murphy, 2003, Detection of FLT3 internal tandem duplication and D835 mutations by a multiplex PCR and capillary electrophoresis assay., J Mol Diagn, 5, 96, 10.1016/S1525-1578(10)60458-8 Harutyunyan, 2011, p53 lesions in leukemic transformation., N Engl J Med, 364, 488, 10.1056/NEJMc1012718 Ernst, 2010, Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders., Nat Genet, 42, 722, 10.1038/ng.621 Nikoloski, 2010, Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes., Nat Genet, 42, 665, 10.1038/ng.620 Oh, 2010, Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms., Blood, 116, 988, 10.1182/blood-2010-02-270108 Pardanani, 2010, LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations., Leukemia, 24, 1713, 10.1038/leu.2010.163 Maciejewski, 2008, Whole genome scanning as a cytogenetic tool in hematologic malignancies., Blood, 112, 965, 10.1182/blood-2008-02-130435 Plo, 2008, JAK2 stimulates homologous recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders., Blood, 112, 1402, 10.1182/blood-2008-01-134114 Rossi, 2007, Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age., Nature, 447, 725, 10.1038/nature05862 Vannucchi, 2007, Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia., Blood, 110, 840, 10.1182/blood-2006-12-064287 Laurie, 2006, Inactivation of the p53 pathway in retinoblastoma., Nature, 444, 61, 10.1038/nature05194 Riemenschneider, 2003, Refined mapping of 1q32 amplicons in malignant gliomas confirms MDM4 as the main amplification target., Int J Cancer, 104, 752, 10.1002/ijc.11023 Beer, 2010, Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm., Blood, 115, 2891, 10.1182/blood-2009-08-236596 Cadieux, 2006, Transgenic mice expressing the p75 CCAAT-displacement protein/Cut homeobox isoform develop a myeloproliferative disease-like myeloid leukemia., Cancer Res, 66, 9492, 10.1158/0008-5472.CAN-05-4230 Truscott, 2008, p110 CUX1 cooperates with E2F transcription factors in the transcriptional activation of cell cycle-regulated genes., Mol Cell Biol, 28, 3127, 10.1128/MCB.02089-07 Banham, 2001, The FOXP1 winged helix transcription factor is a novel candidate tumor suppressor gene on chromosome 3p., Cancer Res, 61, 8820 Kok, 1997, Deletions of the short arm of chromosome 3 in solid tumors and the search for suppressor genes., Adv Cancer Res, 71, 27, 10.1016/S0065-230X(08)60096-2 Hu, 2006, Foxp1 is an essential transcriptional regulator of B cell development., Nat Immunol, 7, 819, 10.1038/ni1358 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 Odero, 2001, Identification of new translocations involving ETV6 in hematologic malignancies by fluorescence in situ hybridization and spectral karyotyping., Genes Chromosomes Cancer, 31, 134, 10.1002/gcc.1127 Bohlander, 2005, ETV6: a versatile player in leukemogenesis., Semin Cancer Biol, 15, 162, 10.1016/j.semcancer.2005.01.008 Cavé, 1997, ETV6 is the target of chromosome 12p deletions in t(12;21) childhood acute lymphocytic leukemia., Leukemia, 11, 1459, 10.1038/sj.leu.2400798 Ding, 2009, AML1/RUNX1 point mutation possibly promotes leukemic transformation in myeloproliferative neoplasms., Blood, 114, 5201, 10.1182/blood-2009-06-223982 Tanaka, 1995, An acute myeloid leukemia gene, AML1, regulates hemopoietic myeloid cell differentiation and transcriptional activation antagonistically by two alternative spliced forms., EMBO J, 14, 341, 10.1002/j.1460-2075.1995.tb07008.x