Abstract
Transformation to acute leukemia is a major complication of myeloproliferative neoplasms (MPNs), however, the genetic changes leading to transformation remain largely unknown. We screened nine patients with post-MPN leukemia for chromosomal aberrations using microarray karyotyping. Deletions on the short arm of chromosome 7 (del7p) emerged as a recurrent defect. We mapped the common deleted region to the IKZF1 gene, which encodes the transcription factor Ikaros. We further examined the frequency of IKZF1 deletions in a total of 29 post-MPN leukemia and 526 MPN patients without transformation and observed a strong association of IKZF1 deletions with post-MPN leukemia in two independent cohorts. Patients with IKZF1 loss showed complex karyotypes, and del7p was a late event in the genetic evolution of the MPN clone. IKZF1 deletions were observed in both undifferentiated and differentiated myeloid cell types, indicating that IKZF1 loss does not cause differentiation arrest but rather renders progenitors susceptible to transformation, most likely through chromosomal instability. Induced Ikzf1 haploinsufficiency in primary murine progenitors resulted in elevated Stat5 phosphorylation and increased cytokine-dependent growth, suggesting that reduced expression of IKZF1 is sufficient to perturb growth regulation. Thus, IKZF1 loss is an important step in the leukemic transformation of a subpopulation of MPN patients.
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References
Campbell P, Green A . The myeloproliferative disorders. N Engl J Med 2006; 355: 2452–2466.
Kralovics R . Genetic complexity of myeloproliferative neoplasms. Leukemia 2008; 22: 1841–1848.
James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434: 1144–1148.
Kralovics R, Passamonti F, Buser A, Teo S, Tiedt R, Passweg J et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352: 1779–1790.
Levine R, Wadleigh M, Cools J, Ebert B, Wernig G, Huntly B et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005; 7: 387–397.
Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054–1061.
Scott L, Tong W, Levine R, Scott M, Beer P, Stratton M et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007; 356: 459–468.
Pietra D, Li S, Brisci A, Passamonti F, Rumi E, Theocharides A et al. Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders. Blood 2008; 111: 1686–1689.
Pikman Y, Lee B, Mercher T, McDowell E, Ebert B, Gozo M et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 2006; 3: e270.
Pardanani A, Levine R, Lasho T, Pikman Y, Mesa R, Wadleigh M et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006; 108: 3472–3476.
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: 6182–6192.
Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Massé A et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009; 360: 2289–2301.
Wolanskyj A, Lasho T, Schwager S, McClure R, Wadleigh M, Lee S et al. JAK2 mutation in essential thrombocythaemia: clinical associations and long-term prognostic relevance. Br J Haematol 2005; 131: 208–213.
Theocharides A, Boissinot M, Girodon F, Garand R, Teo S, Lippert E et al. Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood 2007; 110: 375–379.
Campbell PJ, Baxter EJ, Beer PA, Scott LM, Bench AJ, Huntly BJ et al. Mutation of JAK2 in the myeloproliferative disorders: timing, clonality studies, cytogenetic associations, and role in leukemic transformation. Blood 2006; 108: 3548–3555.
Abdel-Wahab O, Manshouri T, Patel J, Harris K, Yao J, Hedvat C et al. Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias. Cancer Res 2010; 70: 447–452.
Green A, Beer P . Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms. N Engl J Med 2010; 362: 369–370.
Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009; 361: 1058–1066.
Kralovics R, Teo SS, Li S, Theocharides A, Buser AS, Tichelli A et al. Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders. Blood 2006; 108: 1377–1380.
Olcaydu D, Harutyunyan A, Jäger R, Berg T, Gisslinger B, Pabinger I et al. A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat Genet 2009; 41: 450–454.
Moffat J, Grueneberg DA, Yang X, Kim SY, Kloepfer AM, Hinkle G et al. A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen. Cell 2006; 124: 1283–1298.
Zufferey R, Nagy D, Mandel RJ, Naldini L, Trono D . Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nat Biotechnol 1997; 15: 871–875.
Georgopoulos K, Bigby M, Wang J, Molnar A, Wu P, Winandy S et al. The Ikaros gene is required for the development of all lymphoid lineages. Cell 1994; 79: 143–156.
Winandy S, Wu P, Georgopoulos K . A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell 1995; 83: 289–299.
Wang J, Nichogiannopoulou A, Wu L, Sun L, Sharpe A, Bigby M et al. Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity 1996; 5: 537–549.
Kano G, Morimoto A, Takanashi M, Hibi S, Sugimoto T, Inaba T et al. Ikaros dominant negative isoform (Ik6) induces IL-3-independent survival of murine pro-B lymphocytes by activating JAK-STAT and up-regulating Bcl-xl levels. Leuk Lymphoma 2008; 49: 965–973.
Georgopoulos K, Moore D, Derfler B . Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment. Science 1992; 258: 808–812.
Kirstetter P, Thomas M, Dierich A, Kastner P, Chan S . Ikaros is critical for B cell differentiation and function. Eur J Immunol 2002; 32: 720–730.
Lopez RA, Schoetz S, DeAngelis K, O’Neill D, Bank A . Multiple hematopoietic defects and delayed globin switching in Ikaros null mice. Proc Natl Acad Sci USA 2002; 99: 602–607.
Mullighan C, Miller C, Radtke I, Phillips L, Dalton J, Ma J et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 2008; 453: 110–114.
Iacobucci I, Storlazzi C, Cilloni D, Lonetti A, Ottaviani E, Soverini S et al. Identification and molecular characterization of recurrent genomic deletions on 7p12 in the IKZF1 gene in a large cohort of BCR-ABL1-positive acute lymphoblastic leukemia patients: on behalf of Gruppo Italiano Malattie Ematologiche dell’Adulto Acute Leukemia Working Party (GIMEMA AL WP). Blood 2009; 114: 2159–2167.
Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 1998; 92: 2322–2333.
Mesa R, Li C, Ketterling R, Schroeder G, Knudson R, Tefferi A . Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood 2005; 105: 973–977.
Mullighan C, Su X, Zhang J, Radtke I, Phillips L, Miller C et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 2009; 360: 470–480.
Martinelli G, Iacobucci I, Storlazzi C, Vignetti M, Paoloni F, Cilloni D et al. IKZF1 (Ikaros) deletions in BCR-ABL1-positive acute lymphoblastic leukemia are associated with short disease-free survival and high rate of cumulative incidence of relapse: a GIMEMA AL WP report. J Clin Oncol 2009; 27: 5202–5207.
Luna-Fineman S, Shannon KM, Lange BJ . Childhood monosomy 7: epidemiology, biology, and mechanistic implications. Blood 1995; 85: 1985–1999.
Lacronique V, Boureux A, Valle V, Poirel H, Quang C, Mauchauffé M et al. A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science 1997; 278: 1309–1312.
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: 2662–2667.
Griesinger F, Hennig H, Hillmer F, Podleschny M, Steffens R, Pies A et al. A BCR-JAK2 fusion gene as the result of a t(9;22)(p24;q11.2) translocation in a patient with a clinically typical chronic myeloid leukemia. Genes Chromosomes Cancer 2005; 44: 329–333.
Mercher T, Wernig G, Moore S, Levine R, Gu T, Fröhling S et al. JAK2T875N is a novel activating mutation that results in myeloproliferative disease with features of megakaryoblastic leukemia in a murine bone marrow transplantation model. Blood 2006; 108: 2770–2779.
Kearney L, Gonzalez De Castro D, Yeung J, Procter J, Horsley SW, Eguchi-Ishimae M et al. Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia. Blood 2009; 113: 646–648.
Mullighan C, Zhang J, Harvey R, Collins-Underwood J, Schulman B, Phillips L et al. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci USA 2009; 106: 9414–9418.
Acknowledgements
The study was supported by funding from the Austrian Academy of Sciences, the Austrian Science Fund (FWF, P20033-B11) and the MPD Foundation, as well as from AIRC (Associazione Italiana per la Ricerca sul Cancro, Milan), Fondazione Cariplo (Milan), PRIN-MIUR (Rome) and Alleanza Contro il Cancro (Rome), all in Italy. We thank Sebastian Nijman, Markus Muellner and Nils Craig-Mueller for technical assistance and advice and Helen Pickersgill for helpful comments on the paper.
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Jäger, R., Gisslinger, H., Passamonti, F. et al. Deletions of the transcription factor Ikaros in myeloproliferative neoplasms. Leukemia 24, 1290–1298 (2010). https://doi.org/10.1038/leu.2010.99
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DOI: https://doi.org/10.1038/leu.2010.99
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