Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis

Blood - Tập 123 - Trang e123-e133 - 2014
Raajit Rampal1,2,3, Fatima Al-Shahrour4, Omar Abdel-Wahab1,2,3, Jay P. Patel1, Jean-Philippe Brunel5, Craig H. Mermel5,6, Adam J. Bass5,7, Jennifer Pretz5,8, Jihae Ahn1, Todd Hricik1, Outi Kilpivaara9, Martha Wadleigh7, Lambert Busque10,11,12, D. Gary Gilliland13, Todd R. Golub5,14,15, Benjamin L. Ebert5,16, Ross L. Levine1,2,3
1Human Oncology and Pathogenesis Program
2Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY;
3Weill Cornell Medical College, New York, NY
4Translational Bioinformatics Unit, Clinical Research Programme, Spanish National Cancer Research Centre, Madrid, Spain;
5Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, MA;
6Massachusetts General Hospital, Cancer Center and Department of Pathology, Boston, MA;
7Dana-Farber Cancer Institute, Boston, MA
8Dana Farber Cancer Institute, Boston, MA;
9Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland
10Research Centre, Maisonneuve-Rosemont Hospital,
11Department of Hematology, Maisonneuve-Rosemont Hospital, and
12University of Montreal, Montreal, QC, Canada
13Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
14Children’s Hospital, Harvard Medical School, Boston, MA
15Howard Hughes Medical Institute, Chevy Chase, MD; and
16Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

Tóm tắt

Key Points A gene expression profile consistent with activated JAK2 signaling is seen in all MPN patients, including in patients with CALR mutations. Transcriptional profiling discriminates subsets of MPNs based on JAK2V617F allele burden and on the presence of CALR and TET2 mutations.

Tài liệu tham khảo

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 Baxter, 2005, Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders., Lancet, 365, 1054, 10.1016/S0140-6736(05)71142-9 Zhao, 2005, Role of tyrosine kinases and phosphatases in polycythemia vera., Semin Hematol, 42, 221, 10.1053/j.seminhematol.2005.05.019 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 Scott, 2007, JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis., N Engl J Med, 356, 459, 10.1056/NEJMoa065202 Passamonti, 2011, Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations., Blood, 117, 2813, 10.1182/blood-2010-11-316810 Pardanani, 2006, MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients., Blood, 108, 3472, 10.1182/blood-2006-04-018879 Pikman, 2006, MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia., PLoS Med, 3, e270, 10.1371/journal.pmed.0030270 Lasho, 2010, LNK mutations in JAK2 mutation-negative erythrocytosis., N Engl J Med, 363, 1189, 10.1056/NEJMc1006966 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 Verstovsek, 2012, A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis., N Engl J Med, 366, 799, 10.1056/NEJMoa1110557 Harrison, 2012, JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis., N Engl J Med, 366, 787, 10.1056/NEJMoa1110556 Nangalia, 2013, Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2., N Engl J Med, 369, 2391, 10.1056/NEJMoa1312542 Klampfl, 2013, Somatic mutations of calreticulin in myeloproliferative neoplasms., N Engl J Med, 369, 2379, 10.1056/NEJMoa1311347 Levine, 2006, X-inactivation-based clonality analysis and quantitative JAK2V617F assessment reveal a strong association between clonality and JAK2V617F in PV but not ET/MMM, and identifies a subset of JAK2V617F-negative ET and MMM patients with clonal hematopoiesis., Blood, 107, 4139, 10.1182/blood-2005-09-3900 Patel, 2012, Prognostic relevance of integrated genetic profiling in acute myeloid leukemia., N Engl J Med, 366, 1079, 10.1056/NEJMoa1112304 MacConaill, 2009, Profiling critical cancer gene mutations in clinical tumor samples., PLoS ONE, 4, e7887, 10.1371/journal.pone.0007887 Abdel-Wahab, 2009, Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies., Blood, 114, 144, 10.1182/blood-2009-03-210039 Moffat, 2006, A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen., Cell, 124, 1283, 10.1016/j.cell.2006.01.040 Bhattacharjee, 2001, Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses., Proc Natl Acad Sci USA, 98, 13790, 10.1073/pnas.191502998 Bolstad, 2003, A comparison of normalization methods for high density oligonucleotide array data based on variance and bias., Bioinformatics, 19, 185, 10.1093/bioinformatics/19.2.185 Golub, 1999, Molecular classification of cancer: class discovery and class prediction by gene expression monitoring., Science, 286, 531, 10.1126/science.286.5439.531 Hochberg, 1990, More powerful procedures for multiple significance testing., Stat Med, 9, 811, 10.1002/sim.4780090710 Reich, 2006, GenePattern 2.0., Nat Genet, 38, 500, 10.1038/ng0506-500 Gould, 2006, Comparative gene marker selection suite., Bioinformatics, 22, 1924, 10.1093/bioinformatics/btl196 Subramanian, 2005, Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles., Proc Natl Acad Sci USA, 102, 15545, 10.1073/pnas.0506580102 Schuringa, 2004, Enforced activation of STAT5A facilitates the generation of embryonic stem-derived hematopoietic stem cells that contribute to hematopoiesis in vivo., Stem Cells, 22, 1191, 10.1634/stemcells.2004-0033 Goerttler, 2005, Gene expression profiling in polycythaemia vera: overexpression of transcription factor NF-E2., Br J Haematol, 129, 138, 10.1111/j.1365-2141.2005.05416.x Pellagatti, 2003, Gene expression profiling in polycythemia vera using cDNA microarray technology., Cancer Res, 63, 3940 Rice, 2011, Analysis of genomic aberrations and gene expression profiling identifies novel lesions and pathways in myeloproliferative neoplasms., Blood Cancer J, 1, e40, 10.1038/bcj.2011.39 Skov, 2012, Gene expression profiling with principal component analysis depicts the biological continuum from essential thrombocythemia over polycythemia vera to myelofibrosis., Exp Hematol, 40, 771, 10.1016/j.exphem.2012.05.011 Berkofsky-Fessler, 2010, Transcriptional profiling of polycythemia vera identifies gene expression patterns both dependent and independent from the action of JAK2V617F., Clin Cancer Res, 16, 4339, 10.1158/1078-0432.CCR-10-1092 Kralovics, 2005, Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V617F mutation of Jak2., Blood, 106, 3374, 10.1182/blood-2005-05-1889 Puigdecanet, 2008, Gene expression profiling distinguishes JAK2V617F-negative from JAK2V617F-positive patients in essential thrombocythemia., Leukemia, 22, 1368, 10.1038/leu.2008.112 Schwemmers, 2007, JAK2V617F-negative ET patients do not display constitutively active JAK/STAT signaling., Exp Hematol, 35, 1695, 10.1016/j.exphem.2007.07.004 Chen, 2010, Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling., Cancer Cell, 18, 524, 10.1016/j.ccr.2010.10.013 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 Klippel, 2003, Quantification of PRV-1 mRNA distinguishes polycythemia vera from secondary erythrocytosis., Blood, 102, 3569, 10.1182/blood-2003-03-0919 Maxson, 2013, Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML., N Engl J Med, 368, 1781, 10.1056/NEJMoa1214514 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 Herrera-Merchan, 2012, Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease., Nat Commun, 10, 623, 10.1038/ncomms1623 Yan, 2012, Critical requirement for Stat5 in a mouse model of polycythemia vera., Blood, 119, 3539, 10.1182/blood-2011-03-345215 Walz, 2012, Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2(V617F) in mice., Blood, 119, 3550, 10.1182/blood-2011-12-397554 Vainchenker, 2011, New mutations and pathogenesis of myeloproliferative neoplasms., Blood, 118, 1723, 10.1182/blood-2011-02-292102 Shih, 2012, The role of mutations in epigenetic regulators in myeloid malignancies., Nat Rev Cancer, 12, 599, 10.1038/nrc3343 Ko, 2010, Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2., Nature, 468, 839, 10.1038/nature09586 Pronier, 2011, Inhibition of TET2-mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine disturbs erythroid and granulomonocytic differentiation of human hematopoietic progenitors., Blood, 118, 2551, 10.1182/blood-2010-12-324707 Ko, 2011, Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice., Proc Natl Acad Sci USA, 108, 14566, 10.1073/pnas.1112317108 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 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 Li, 2011, Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies., Blood, 118, 4509, 10.1182/blood-2010-12-325241 Jamieson, 2006, The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation., Proc Natl Acad Sci USA, 103, 6224, 10.1073/pnas.0601462103 Akada, 2010, Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease., Blood, 115, 3589, 10.1182/blood-2009-04-215848 Tefferi, 2006, The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera., Cancer, 106, 631, 10.1002/cncr.21645 Carbuccia, 2009, Mutations of ASXL1 gene in myeloproliferative neoplasms., Leukemia, 23, 2183, 10.1038/leu.2009.141 Delhommeau, 2009, Mutation in TET2 in myeloid cancers., N Engl J Med, 360, 2289, 10.1056/NEJMoa0810069 Tefferi, 2009, Mutation in TET2 in myeloid cancers., N Engl J Med Schaub, 2010, Clonal analysis of TET2 and JAK2 mutations suggests that TET2 can be a late event in the progression of myeloproliferative neoplasms., Blood, 115, 2003, 10.1182/blood-2009-09-245381 Zhang, 2012, Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome., Blood, 119, 4480, 10.1182/blood-2011-11-390252 Beer, 2010, Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm., Blood, 115, 2891, 10.1182/blood-2009-08-236596 Abdel-Wahab, 2010, Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias., Cancer Res, 70, 447, 10.1158/0008-5472.CAN-09-3783 Fiskus, 2013, Dual PI3K/AKT/mTOR inhibitor BEZ235 synergistically enhances the activity of JAK2 inhibitor against cultured and primary human myeloproliferative neoplasm cells., Mol Cancer Ther, 12, 577, 10.1158/1535-7163.MCT-12-0862 Bartalucci, 2013, Co-targeting the PI3K/mTOR and JAK2 signalling pathways produces synergistic activity against myeloproliferative neoplasms., J Cell Mol Med, 17, 1385, 10.1111/jcmm.12162 Guglielmelli, 2011, Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis., Blood, 118, 2069, 10.1182/blood-2011-01-330563