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−7/7q− syndrome in myeloid-lineage hematopoietic malignancies: attempts to understand this complex disease entity

Abstract

The recurrence of chromosomal abnormalities in a specific subtype of cancer strongly suggests that dysregulated gene expression in the corresponding region has a critical role in disease pathogenesis. −7/7q−, defined as the entire loss of chromosome 7 and partial deletion of its long arm, is among the most frequently observed chromosomal aberrations in myeloid-lineage hematopoietic malignancies such as myelodysplastic syndrome and acute myeloid leukemia, particularly in patients treated with cytotoxic agents and/or irradiation. Tremendous efforts have been made to clarify the molecular mechanisms underlying the disease development, and several possible candidate genes have been cloned. However, the study is still underway, and the entire nature of this syndrome is not completely understood. In this review, we focus on the attempts to identify commonly deleted regions in patients with −7/7q−; isolate the candidate genes responsible for disease development, cooperative genes and the factors affecting disease prognosis; and determine effective and potent therapeutic approaches. We also refer to the possibility that the accumulation of multiple gene haploinsufficiency, rather than the loss of a single tumor suppressor gene, may contribute to the development of diseases with large chromosomal deletions such as −7/7q−.

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References

  1. Chen J, Odenike O, Rowley JD . Leukaemogenesis: more than mutant genes. Nat Rev Cancer 2010; 10: 23–36.

    CAS  Google Scholar 

  2. Johnson E, Cotter FE . Monosomy 7 and 7q—associated with myeloid malignancy. Blood Rev 1997; 11: 46–55.

    CAS  Google Scholar 

  3. Hasle H, Aricò M, Basso G, Biondi A, Cantù Rajnoldi A, Creutzig U et al. Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7. European Working Group on MDS in Childhood (EWOG-MDS). Leukemia 1999; 13: 376–385.

    CAS  Google Scholar 

  4. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000; 96: 4075–4083.

    CAS  Google Scholar 

  5. Hussain FT, Nguyen EP, Raza S, Knudson R, Pardanani A, Hanson CA et al. Sole abnormalities of chromosome 7 in myeloid malignancies: spectrum, histopathologic correlates, and prognostic implications. Am J Hematol 2012; 87: 684–686.

    CAS  Google Scholar 

  6. Luna-Fineman S, Shannon KM, Atwater SK, Davis J, Masterson M, Ortega J et al. Myelodysplastic and myeloproliferative disorders of childhood: a study of 167 patients. Blood 1999; 93: 459–466.

    CAS  Google Scholar 

  7. Hasle H, Alonzo TA, Auvrignon A, Behar C, Chang M, Creutzig U et al. Monosomy 7 and deletion 7q in children and adolescents with acute myeloid leukemia: an international retrospective study. Blood 2007; 109: 4641–4647.

    CAS  Google Scholar 

  8. Pedersen-Bjergaard J, Andersen MK, Andersen MT, Christiansen DH . Genetics of therapy-related myelodysplasia and acute myeloid leukemia. Leukemia 2008; 22: 240–248.

    CAS  Google Scholar 

  9. Qian Z, Joslin JM, Tennant TR, Reshmi SC, Young DJ, Stoddart A et al. Cytogenetic and genetic pathways in therapy-related acute myeloid leukemia. Chem Biol Interact 2010; 184: 50–57.

    CAS  Google Scholar 

  10. Kawankar N, Vundinti BR . Cytogenetic abnormalities in myelodysplastic syndrome: an overview. Hematology 2011; 16: 131–138.

    Google Scholar 

  11. Navarro JT, Feliu E, Grau J, Espinet B, Colomer D, Ribera JM et al. Monosomy 7 with severe myelodysplasia developing during imatinib treatment of Philadelphia-positive chronic myeloid leukemia: two cases with a different outcome. Am J Hematol 2007; 82: 849–851.

    Google Scholar 

  12. Larsson N, Billström R, Lilljebjörn H, Lassen C, Richter J, Ekblom M et al. Genetic analysis of dasatinib-treated chronic myeloid leukemia rapidly developing into acute myeloid leukemia with monosomy 7 in Philadelphia-negative cells. Cancer Genet Cytogenet 2010; 199: 89–95.

    CAS  Google Scholar 

  13. Groves MJ, Sales M, Baker L, Griffiths M, Pratt N, Tauro S . Factors influencing a second myeloid malignancy in patients with Philadelphia-negative −7 or del(7q) clones during tyrosine kinase inhibitor therapy for chronic myeloid leukemia. Cancer Genet 2011; 204: 39–44.

    CAS  Google Scholar 

  14. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079–2088.

    CAS  Google Scholar 

  15. Germing U, Hildebrandt B, Pfeilstöcker M, Nösslinger T, Valent P, Fonatsch C et al. Refinement of the international prognostic scoring system (IPSS) by including LDH as an additional prognostic variable to improve risk assessment in patients with primary myelodysplastic syndromes (MDS). Leukemia 2005; 19: 2223–2231.

    CAS  Google Scholar 

  16. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010; 116: 354–365.

    Article  CAS  Google Scholar 

  17. Tong WG, Quintás-Cardama A, Kadia T, Borthakur G, Jabbour E, Ravandi F et al. Predicting survival of patients with hypocellular myelodysplastic syndrome: development of a disease-specific prognostic score system. Cancer 2012; 118: 4462–4470.

    Google Scholar 

  18. Freireich E, Whang J, Tjio JH, Levin RH, Brittin GM, Frei E . Refractory anemia, granulocytic hyperplasia of bone marrow and a missing chromosome in marrow cells. A new clinical syndrome? Clin Res 1964; 12: 284.

    Google Scholar 

  19. Rowley JD, Blaisdell RK, Jacobson LO . Chromosome studies in preleukemia: I. Aneuploidy of group C chromosomes in three patients. Blood 1966; 27: 782–799.

    CAS  Google Scholar 

  20. Rowley JD . Letter: Deletions of chromosome 7 in haematological disorders. Lancet 1973; 2: 1385–1386.

    CAS  Google Scholar 

  21. Bernstein R, Philip P, Ueshima Y . Fourth International Workshop on Chromosomes in Leukemia 1982: abnormalities of chromosome 7 resulting in monosomy 7 or in deletion of the long arm (7q-): review of translocations, breakpoints, and associated abnormalities. Cancer Genet Cytogenet 1984; 11: 300–303.

    CAS  Google Scholar 

  22. Kere J, Ruutu T, Lahtinen R, de la Chapelle A . Molecular characterization of chromosome 7 long arm deletions in myeloid disorders. Blood 1987; 70: 1349–1353.

    CAS  Google Scholar 

  23. Lewis S, Abrahamson G, Boultwood J, Fidler C, Potter A, Wainscoat JS . Molecular characterization of the 7q deletion in myeloid disorders. Br J Haematol 1996; 93: 75–80.

    CAS  Google Scholar 

  24. Le Beau MM, Espinosa R r, Davis EM, Eisenbart JD, Larson RA, Green ED . Cytogenetic and molecular delineation of a region of chromosome 7 commonly deleted in malignant myeloid diseases. Blood 1996; 88: 1930–1935.

    CAS  Google Scholar 

  25. Tosi S, Harbott J, Haas OA, Douglas A, Hughes DM, Ross FM et al. Classification of deletions and identification of cryptic translocations involving 7q by fluorescence in situ hybridization (FISH). Leukemia 1996; 10: 644–649.

    CAS  Google Scholar 

  26. Fischer K, Fröhling S, Scherer SW, McAllister Brown J, Scholl C, Stilgenbauer S et al. Molecular cytogenetic delineation of deletions and translocations involving chromosome band 7q22 in myeloid leukemias. Blood 1997; 89: 2036–2041.

    CAS  Google Scholar 

  27. Döhner K, Brown J, Hehmann U, Hetzel C, Stewart J, Lowther G et al. Molecular cytogenetic characterization of a critical region in bands 7q35-q36 commonly deleted in malignant myeloid disorders. Blood 1998; 92: 4031–4035.

    Google Scholar 

  28. Brezinová J, Zemanová Z, Ransdorfová S, Pavlistová L, Babická L, Housková L et al. Structural aberrations of chromosome 7 revealed by a combination of molecular cytogenetic techniques in myeloid malignancies. Cancer Genet Cytogenet 2007; 173: 10–16.

    Google Scholar 

  29. Kiuru-Kuhlefelt S, Kristo P, Ruutu T, Knuutila S, Kere J . Evidence for two molecular steps in the pathogenesis of myeloid disorders associated with deletion of chromosome 7 long arm. Leukemia 1997; 11: 2097–2104.

    CAS  Google Scholar 

  30. Liang H, Fairman J, Claxton DF, Nowell PC, Green ED, Nagarajan L . Molecular anatomy of chromosome 7q deletions in myeloid neoplasms: evidence for multiple critical loci. Proc Natl Acad Sci USA 1998; 95: 3781–3785.

    CAS  Google Scholar 

  31. Asou H, Matsui H, Ozaki Y, Nagamachi A, Nakamura M, Aki D et al. Identification of a common microdeletion cluster in 7q21.3 subband among patients with myeloid leukemia and myelodysplastic syndrome. Biochem Biophys Res Commun 2009; 383: 245–251.

    CAS  Google Scholar 

  32. De Weer A, Poppe B, Vergult S, Van Vlierberghe P, Petrick M, De Bock R et al. Identification of two critically deleted regions within chromosome segment 7q35-q36 in EVI1 deregulated myeloid leukemia cell lines. PLoS ONE 2010; 5: e8676.

    Google Scholar 

  33. Jerez A, Sugimoto Y, Makishima H, Verma A, Jankowska AM, Przychodzen B et al. Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis. Blood 2012; 119: 6109–6117.

    CAS  Google Scholar 

  34. McNerney ME, Brown CD, Wang X, Bartom ET, Karmakar S, Bandlamudi C et al. CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia. Blood 2013; 121: 975–983.

    CAS  Google Scholar 

  35. Hosono N, Makishima H, Jerez A, Yoshida K, Przychodzen B, McMahon S et al. Recurrent genetic defects on chromosome 7q in myeloid neoplasms. Leukemia 2014; 28: 1348–1351.

    CAS  Google Scholar 

  36. Cao R, Wan gL, Wang H, Xia L, Erdjument-Bromage H, Tempst P et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 2002; 298: 1039–1043.

    CAS  Google Scholar 

  37. Czermin B, Melfi R, McCabe D, Seitz V, Imhof A, Pirrotta V . Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell 2002; 111: 185–196.

    CAS  Google Scholar 

  38. Müller J, Hart CM, Francis NJ, Vargas ML, Sengupta A, Wild B et al. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell 2002; 111: 197–208.

    Google Scholar 

  39. Simon JA, Kingston RE . Mechanisms of polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol 2009; 10: 697–708.

    CAS  Google Scholar 

  40. Margueron R, Reinberg D . The Polycomb complex PRC2 and its mark in life. Nature 2011; 469: 343–349.

    Article  CAS  Google Scholar 

  41. Nikoloski G, Langemeijer SM, Kuiper RP, Knops R, Massop M, Tönnissen ER et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet 2010; 42: 665–667.

    CAS  Google Scholar 

  42. 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: 722–726.

    CAS  Google Scholar 

  43. Wang X, Dai H, Wang Q, Wang Q, Xu Y, Wang Y et al. EZH2 mutations are related to low blast percentage in bone marrow and -7/del(7q) in de novo acute myeloid leukemia. PLoS ONE 2013; 8: e61341.

    CAS  Google Scholar 

  44. Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G et al. Clinical effect of point mutations in myelodysplastic syndromes. New Engl J Med 2011; 364: 2496–2506.

    CAS  Google Scholar 

  45. Bejar R, Stevenson KE, Caughey BA, Abdel-Wahab O, Steensma DP, Galili N et al. Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes. J Clin Oncol 2012; 30: 3376–3382.

    Google Scholar 

  46. Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366: 1079–1089.

    CAS  Google Scholar 

  47. Simon C, Chagraoui J, Krosl J, Gendron P, Wilhelm B, Lemieux S et al. A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. Genes Dev 2012; 26: 651–656.

    CAS  Google Scholar 

  48. Muto T, Sashida G, Oshima M, Wendt GR, Mochizuki-Kashio M, Nagata Y et al. Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders. J Exp Med 2013; 210: 2627–2639.

    CAS  Google Scholar 

  49. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet 2010; 42: 181–185.

    Article  CAS  Google Scholar 

  50. Sneeringer CJ, Scott MP, Kuntz KW, Knutson SK, Pollock RM, Richon VM et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc Natl Acad Sci USA 2010; 107: 20980–20985.

    CAS  Google Scholar 

  51. Yap DB, Chu J, Berg T, Schapira M, Cheng SW, Moradian A et al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood 2011; 117: 2451–2459.

    CAS  Google Scholar 

  52. Herrera-Merchan A, Arranz L, Ligos JM, de Molina A, Dominguez O, Gonzalez S . Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease. Nat Commun 2012; 3: 623.

    CAS  Google Scholar 

  53. Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL et al. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev 2007; 21: 1050–1063.

    CAS  Google Scholar 

  54. McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 2012; 492: 108–112.

    CAS  Google Scholar 

  55. Li CF, MacDonald JR, Wei RY, Ray J, Lau K, Kandel C et al. Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse. BMC Genomics 2007; 8: 92.

    Google Scholar 

  56. Topaz O, Indelman M, Chefetz I, Geiger D, Metzker A, Altschuler Y et al. A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis. Am J Hum Genet 2006; 79: 759–764.

    CAS  Google Scholar 

  57. Nagamachi A, Matsui H, Asou H, Ozaki Y, Aki D, Kanai A et al. Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7. Cancer Cell 2013; 24: 305–317.

    CAS  Google Scholar 

  58. Takaya A, Kamio T, Masuda M, Mochizuki N, Sawa H, Sato M et al. R-Ras regulates exocytosis by Rgl2/Rlf-mediated activation of RalA on endosomes. Mol Biol Cell 2007; 18: 1850–1860.

    CAS  Google Scholar 

  59. Hershkovitz D, Gross Y, Nahum S, Yehezkel S, Sarig O, Uitto J et al. Functional characterization of SAMD9, a protein deficient in normophosphatemic familial tumoral calcinosis. J Invest Dermatol 2011; 131: 662–669.

    CAS  Google Scholar 

  60. Hulea L, Nepveu A . CUX1 transcription factors: from biochemical activities and cell-based assays to mouse models and human diseases. Gene 2012; 497: 18–26.

    CAS  Google Scholar 

  61. Sansregret L, Nepveu A . The multiple roles of CUX1: insights from mouse models and cell-based assays. Gene 2008; 412: 84–94.

    CAS  Google Scholar 

  62. Michl P, Ramjaun AR, Pardo OE, Warne PH, Wagner M, Poulsom R et al. CUTL1 is a target of TGF(beta) signaling that enhances cancer cell motility and invasiveness. Cancer Cell 2005; 7: 521–532.

    CAS  Google Scholar 

  63. Ripka S, König A, Buchholz M, Wagner M, Sipos B, Klöppel G et al. WNT5A—target of CUTL1 and potent modulator of tumor cell migration and invasion in pancreatic cancer. Carcinogenesis 2007; 28: 1178–1187.

    CAS  Google Scholar 

  64. Li T, Wang H, Sun Y, Zhao L, Gang Y, Guo X et al. Transcription factor CUTL1 is a negative regulator of drug resistance in gastric cancer. J Biol Chem 2013; 288: 4135–4147.

    CAS  Google Scholar 

  65. Cadieux C, Fournier S, Peterson AC, Bédard C, Bedell BJ, Nepveu A . Transgenic mice expressing the p75 CCAAT-displacement protein/Cut homeobox isoform develop a myeloproliferative disease-like myeloid leukemia. Cancer Res 2006; 66: 9492–9501.

    CAS  Google Scholar 

  66. Cadieux C, Kedinger V, Yao L, Vadnais C, Drossos M, Paquet M et al. Mouse mammary tumor virus p75 and p110 CUX1 transgenic mice develop mammary tumors of various histologic types. Cancer Res 2009; 69: 7188–7197.

    CAS  Google Scholar 

  67. Sinclair AM, Lee JA, Goldstein A, Xing D, Liu S, Ju R et al. Lymphoid apoptosis and myeloid hyperplasia in CCAAT displacement protein mutant mice. Blood 2001; 98: 3658–3667.

    CAS  Google Scholar 

  68. Scherer SW, Neufeld EJ, Lievens PM, Orkin SH, Kim J, Tsui LC . Regional localization of the CCAAT displacement protein gene (CUTL1) to 7q22 by analysis of somatic cell hybrids. Genomics 1993; 15: 695–696.

    CAS  Google Scholar 

  69. Lemieux N, Zhang XX, Dufort D, Nepveu A . Assignment of the human homologue of the Drosophila Cut homeobox gene (CUTL1) to band 7q22 by fluorescence in situ hybridization. Genomics 1994; 24: 191–193.

    CAS  Google Scholar 

  70. Tosi S, Scherer SW, Giudic G, Czepulkowski B, Biondi A, Kearney L . Delineation of multiple deleted regions in 7q in myeloid disorders. Genes Chromosomes Cancer 1999; 25: 384–392.

    CAS  Google Scholar 

  71. Wong CC, Martincorena I, Rust AG, Rashid M, Alifrangis C, Alexandrov LB et al. Inactivating CUX1 mutations promote tumorigenesis. Nat Genet 2014; 46: 33–38.

    CAS  Google Scholar 

  72. Ansari KI, Mandal SS . Mixed lineage leukemia: roles in gene expression, hormone signaling and mRNA processing. FEBS J 2010; 277: 1790–1804.

    CAS  Google Scholar 

  73. Herz HM, Hu D, Shilatifard A . Enhancer malfunction in cancer. Mol Cell 2014; 53: 859–866.

    CAS  Google Scholar 

  74. Kühn MW, Radtke I, Bullinger L, Goorha S, Cheng J, Edelmann J et al. High-resolution genomic profiling of adult and pediatric core-binding factor acute myeloid leukemia reveals new recurrent genomic alterations. Blood 2012; 119: e67–e75.

    Google Scholar 

  75. Dolnik A, Engelmann JC, Scharfenberger-Schmeer M, Mauch J, Kelkenberg-Schade S, Haldemann B et al. Commonly altered genomic regions in acute myeloid leukemia are enriched for somatic mutations involved in chromatin remodeling and splicing. Blood 2012; 120: e83–e92.

    CAS  Google Scholar 

  76. Gui Y, Guo G, Huang Y, Hu X, Tang A, Gao S et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat Genet 2011; 43: 875–858.

    CAS  Google Scholar 

  77. Parsons DW, Li M, Zhang X, Jones S, Leary RJ, Lin JC et al. The genetic landscape of the childhood cancer medulloblastoma. Science 2011; 331: 435–439.

    CAS  Google Scholar 

  78. Zang ZJ, Cutcutache I, Poon SL, Zhang SL, McPherson JR, Tao J et al. Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat Genet 2012; 44: 570–574.

    CAS  Google Scholar 

  79. Song Y, Li L, Ou Y, Gao Z, Li E, Li X et al. Identification of genomic alterations in oesophageal squamous cell cancer. Nature 2014; 509: 91–95.

    CAS  Google Scholar 

  80. Ruault M, Brun ME, Ventura M, Roizès G, De Sario A . MLL3, a new human member of the TRX/MLL gene family, maps to 7q36, a chromosome region frequently deleted in myeloid leukaemia. Gene 2002; 284: 73–81.

    CAS  Google Scholar 

  81. Chen C, Liu Y, Rappaport AR, Kitzing T, Schultz N, Zhao Z et al. MLL3 Is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. Cancer Cell 2014; 25: 652–665.

    Google Scholar 

  82. Somervaille TC, Matheny CJ, Spencer GJ, Iwasaki M, Rinn JL, Witten DM et al. Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells. Cell Stem Cell 2009; 4: 129–140.

    CAS  Google Scholar 

  83. Pellagatti A, Cazzola M, Giagounidis A, Perry J, Malcovati L, Della Porta MG et al. Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells. Leukemia 2010; 24: 756–764.

    CAS  Google Scholar 

  84. Estey EH . Epigenetics in clinical practice: the examples of azacitidine and decitabine in myelodysplasia and acute myeloid leukemia. Leukemia 2013; 27: 1803–1812.

    CAS  Google Scholar 

  85. Zhou L, Opalinska J, Sohal D, Yu Y, Mo Y, Bhagat T et al. Aberrant epigenetic and genetic marks are seen in myelodysplastic leukocytes and reveal Dock4 as a candidate pathogenic gene on chromosome 7q. J Biol Chem 2011; 286: 25211–25223.

    CAS  Google Scholar 

  86. Kjeldsen E, Veigaard C . DOCK4 deletion at 7q31.1 in a de novo acute myeloid leukemia with a normal karyotype. Cell Oncol (Dordr) 2013; 36: 395–403.

    Google Scholar 

  87. Yajnik V, Paulding C, Sordella R, McClatchey AI, Saito M, Wahrer DC et al. DOCK4, a GTPase activator, is disrupted during tumorigenesis. Cell 2003; 112: 672–684.

    Google Scholar 

  88. Glöckner G, Scherer S, Schattevoy R, Boright A, Weber J, Tsui LC et al. Large-scale sequencing of two regions in human chromosome 7q22: analysis of 650 kb of genomic sequence around the EPO and CUTL1 loci reveals 17 genes. Genome Res 1998; 8: 1060–1073.

    Google Scholar 

  89. Kratz CP, Emerling BM, Donovan S, Laig-Webster M, Taylor BR, Thompson P et al. Candidate gene isolation and comparative analysis of a commonly deleted segment of 7q22 implicated in myeloid malignancies. Genomics 2001; 77: 171–180.

    CAS  Google Scholar 

  90. Kratz CP, Emerling BM, Bonifas J, Wang W, Green ED, Le Beau MM et al. Genomic structure of the PIK3CG gene on chromosome band 7q22 and evaluation as a candidate myeloid tumor suppressor. Blood 2002; 99: 372–374.

    CAS  Google Scholar 

  91. Emerling BM, Bonifas J, Kratz CP, Donovan S, Taylor BR, Green ED et al. MLL5, a homolog of Drosophila trithorax located within a segment of chromosome band 7q22 implicated in myeloid leukemia. Oncogene 2002; 21: 4849–4854.

    CAS  Google Scholar 

  92. Curtiss NP, Bonifas JM, Lauchle JO, Balkman JD, Kratz CP, Emerling BM et al. Isolation and analysis of candidate myeloid tumor suppressor genes from a commonly deleted segment of 7q22. Genomics 2005; 85: 600–607.

    CAS  Google Scholar 

  93. Chen Z, Pasquini M, Hong B, DeHart S, Heikens M, Tsai S . The human Penumbra gene is mapped to a region on chromosome 7 frequently deleted in myeloid malignancies. Cancer Genet Cytogenet 2005; 162: 95–98.

    CAS  Google Scholar 

  94. Singh H, Lane AA, Correll M, Przychodzen B, Sykes DB, Stone RM et al. Putative RNA-splicing gene LUC7L2 on 7q34 represents a candidate gene in pathogenesis of myeloid malignancies. Blood Cancer J 2013; 3: e117.

    CAS  Google Scholar 

  95. Howell VM, Jones JM, Bergren SK, Li L, Billi AC, Avenarius MR et al. Evidence for a direct role of the disease modifier SCNM1 in splicing. Hum Mol Genet 2007; 16: 2506–2516.

    CAS  Google Scholar 

  96. 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: 64–69.

    CAS  Google Scholar 

  97. 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: 3203–3210.

    CAS  Google Scholar 

  98. Zeng WR, Watson P, Lin J, Jothy S, Lidereau R, Park M et al. Refined mapping of the region of loss of heterozygosity on the long arm of chromosome 7 in human breast cancer defines the location of a second tumor suppressor gene at 7q22 in the region of the CUTL1 gene. Oncogene 1999; 18: 2015–2021.

    CAS  Google Scholar 

  99. Haase D, Germing U, Schanz J, Pfeilstöcker M, Nösslinger T, Hildebrandt B et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood 2007; 110: 4385–4395.

    CAS  Google Scholar 

  100. Pozdnyakova O, Miron PM, Tang G, Walter O, Raza A, Woda B et al. Cytogenetic abnormalities in a series of 1,029 patients with primary myelodysplastic syndromes: a report from the US with a focus on some undefined single chromosomal abnormalities. Cancer 2008; 113: 3331–3340.

    Google Scholar 

  101. Cordoba I, González-Porras JR, Nomdedeu B, Luño E, de Paz R, Such E et al. Better prognosis for patients with del(7q) than for patients with monosomy 7 in myelodysplastic syndrome. Cancer 2012; 118: 127–133.

    CAS  Google Scholar 

  102. Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012; 120: 2454–2465.

    CAS  Google Scholar 

  103. Slovak ML, O'Donnel lM, Smith DD, Gaal K . Does MDS with der(1;7)(q10;p10) constitute a distinct risk group? A retrospective single institutional analysis of clinical/pathologic features compared to -7/del(7q) MDS. Cancer Genet Cytogenet 2009; 193: 78–85.

    CAS  Google Scholar 

  104. Göhring G, Michalova K, Beverloo H, Betts D, Harbott J, Haas OA et al. Complex karyotype newly defined: the strongest prognostic factor in advanced childhood myelodysplastic syndrome. Blood 2010; 116: 3766–3769.

    Google Scholar 

  105. Nucifora G, Laricchia-Robbio L, Senyuk V . EVI1 and hematopoietic disorders: history and perspectives. Gene 2006; 368: 1–11.

    CAS  Google Scholar 

  106. Wieser R . The oncogene and developmental regulator EVI1: expression, biochemical properties, and biological functions. Gene 2007; 369: 346–357.

    Google Scholar 

  107. Yoshimi A, Kurokawa M . Evi1 forms a bridge between the epigenetic machinery and signaling pathways. Oncotarget 2011; 2: 575–586.

    Google Scholar 

  108. Glass C, Wilson M, Gonzalez R, Zhang Y, Perkins AS . The role of EVI1 in myeloid malignancies. Blood Cells Mol Dis 2014; 53: 67–76.

    CAS  Google Scholar 

  109. Morishita K, Parker DS, Mucenski ML, Jenkins NA, Copeland NG, Ihle JN . Retroviral activation of a novel gene encoding a zinc finger protein in IL-3-dependent myeloid leukemia cell lines. Cell 1988; 54: 831–840.

    CAS  Google Scholar 

  110. Akagi K, Suzuki T, Stephens RM, Jenkins NA, Copeland NG . RTCGD: retroviral tagged cancer gene database. Nucleic Acids Res 2004; 32 (Database issue): D523–D527.

    CAS  Google Scholar 

  111. Russell M, List A, Greenberg P, Woodward S, Glinsmann B, Parganas E et al. Expression of EVI1 in myelodysplastic syndromes and other hematologic malignancies without 3q26 translocations. Blood 1994; 84: 1243–1248.

    CAS  Google Scholar 

  112. Cuenco GM, Ren R . Both AML1 and EVI1 oncogenic components are required for the cooperation of AML1/MDS1/EVI1 with BCR/ABL in the induction of acute myelogenous leukemia in mice. Oncogene 2004; 23: 569–579.

    CAS  Google Scholar 

  113. Buonamici S, Li D, Chi Y, Zhao R, Wang X, Brace L et al. EVI1 induces myelodysplastic syndrome in mice. J Clin Invest 2004; 114: 713–179.

    CAS  Google Scholar 

  114. Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, van Putten WL, Valk PJ, van der Poel-van de Luytgaarde S, Hack R et al. High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients. Blood 2003; 101: 837–845.

    Google Scholar 

  115. Balgobind BV, Lugthart S, Hollink IH, Arentsen-Peters ST, van Wering ER, de Graaf SS et al. EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia. Leukemia 2010; 24: 942–949.

    CAS  Google Scholar 

  116. Lugthart S, Gröschel S, Beverloo HB, Kayser S, Valk PJ, van Zelderen-Bhola SL et al. Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia. J Clin Oncol 2010; 28: 3890–3898.

    Google Scholar 

  117. Gröschel S, Lugthart S, Schlenk RF, Valk PJ, Eiwen K, Goudswaard C et al. High EVI1 expression predicts outcome in younger adult patients with acute myeloid leukemia and is associated with distinct cytogenetic abnormalities. J Clin Oncol 2010; 28: 2101–2107.

    Google Scholar 

  118. Stein S, Ott MG, Schultze-Strasser S, Jauch A, Burwinkel B, Kinner A et al. Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat Med 2010; 16: 198–204.

    CAS  Google Scholar 

  119. Spensberger D, Delwel R . A novel interaction between the proto-oncogene Evi1 and histone methyltransferases, SUV39H1 and G9a. FEBS Lett 2008; 582: 2761–2767.

    CAS  Google Scholar 

  120. Cattaneo F, Nucifora G . EVI1 recruits the histone methyltransferase SUV39H1 for transcription repression. J Cell Biochem 2008; 105: 344–352.

    CAS  Google Scholar 

  121. Gil J, Peters G . Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol 2006; 7: 667–677.

    CAS  Google Scholar 

  122. Wolff L, Bies J . p15Ink4b Functions in determining hematopoietic cell fates: Implications for its role as a tumor suppressor. Blood Cells Mol Dis 2013; 50: 227–231.

    CAS  Google Scholar 

  123. Ortega S, Malumbres M, Barbacid M . Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim Biophys Acta 2002; 1602: 73–87.

    CAS  Google Scholar 

  124. Latres E, Malumbres M, Sotillo R, Martín J, Ortega S, Martín-Caballero J et al. Limited overlapping roles of P15(INK4b) and P18(INK4c) cell cycle inhibitors in proliferation and tumorigenesis. EMBO J 2000; 19: 3496–3506.

    CAS  Google Scholar 

  125. Krimpenfort P, Quon KC, Mooi WJ, Loonstra A, Berns A . Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature 2001; 413: 83–86.

    CAS  Google Scholar 

  126. Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ et al. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 2001; 413: 86–91.

    CAS  Google Scholar 

  127. Krimpenfort P, Ijpenberg A, Song JY, van der Valk M, Nawijn M, Zevenhoven J et al. p15Ink4b is a critical tumour suppressor in the absence of p16Ink4a. Nature 2007; 448: 943–946.

    CAS  Google Scholar 

  128. Ogawa S, Hirano N, Sato N, Takahashi T, Hangaishi A, Tanaka K et al. Homozygous loss of the cyclin-dependent kinase 4-inhibitor (p16) gene in human leukemias. Blood 1994; 84: 2413–2415.

    Google Scholar 

  129. Quesnel B, Preudhomme C, Philippe N, Vanrumbeke M, Dervite I, Lai JL et al. p16 gene homozygous deletions in acute lymphoblastic leukemia. Blood 1995; 85: 667–663.

    Google Scholar 

  130. Herman JG, Jen J, Merlo A, Baylin SB . Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. Cancer Res 1996; 56: 722–727.

    CAS  Google Scholar 

  131. Uchida T, Kinoshita T, Nagai H, Nakahara Y, Saito H, Hotta T et al. Hypermethylation of the p15INK4B gene in myelodysplastic syndromes. Blood 1997; 90: 1403–1409.

    CAS  Google Scholar 

  132. Wong IH, Ng MH, Huang DP, Lee JC . Aberrant p15 promoter methylation in adult and childhood acute leukemias of nearly all morphologic subtypes: potential prognostic implications. Blood 2000; 95: 1942–1949.

    CAS  Google Scholar 

  133. Quesnel B, Guillerm G, Vereecque R, Wattel E, Preudhomme C, Bauters F et al. Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression. Blood 1998; 91: 2985–2990.

    CAS  Google Scholar 

  134. Tien HF, Tang JH, Tsay W, Liu MC, Lee FY, Wang CH et al. Methylation of the p15(INK4B) gene in myelodysplastic syndrome: it can be detected early at diagnosis or during disease progression and is highly associated with leukaemic transformation. Br J Haematol 2001; 112: 148–154.

    CAS  Google Scholar 

  135. Christiansen DH, Andersen MK, Pedersen-Bjergaard J . Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia. Leukemia 2003; 17: 1813–1819.

    CAS  Google Scholar 

  136. Kim M, Oh B, Kim SY, Park HK, Hwang SM, Kim TY et al. p15INK4b methylation correlates with thrombocytopenia, blast percentage, and survival in myelodysplastic syndromes in a dose dependent manner: quantitation using pyrosequencing study. Leuk Res 2010; 34: 718–722.

    CAS  Google Scholar 

  137. Au WY, Fung A, Man C, Ma SK, Wan TS, Liang R et al. Aberrant p15 gene promoter methylation in therapy-related myelodysplastic syndrome and acute myeloid leukaemia: clinicopathological and karyotypic associations. Br J Haematol 2003; 120: 1062–1065.

    CAS  Google Scholar 

  138. Voso MT, D'Alò F, Greco M, Fabiani E, Criscuolo M, Migliara G et al. Epigenetic changes in therapy-related MDS/AML. Chem Biol Interact 2010; 184: 46–49.

    CAS  Google Scholar 

  139. Blyth K, Cameron ER, Neil JC . The RUNX genes: gain or loss of function in cancer. Nat Rev Cancer 2005; 5: 376–387.

    CAS  Google Scholar 

  140. Mikhail FM, Sinha KK, Saunthararajah Y, Nucifora G . Normal and transforming functions of RUNX1: a perspective. J Cell Physiol 2006; 207: 582–593.

    CAS  Google Scholar 

  141. Ito Y . RUNX genes in development and cancer: regulation of viral gene expression and the discovery of RUNX family genes. Adv Cancer Res 2008; 99: 33–76.

    CAS  Google Scholar 

  142. Ichikawa M, Yoshimi A, Nakagawa M, Nishimoto N, Watanabe-Okochi N, Kurokawa M . A role for RUNX1 in hematopoiesis and myeloid leukemia. Int J Hematol 2013; 97: 726–734.

    CAS  Google Scholar 

  143. Ito Y . Oncogenic potential of the RUNX gene family: 'overview'. Oncogene 2004; 23: 4198–4208.

    CAS  Google Scholar 

  144. Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR . AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 1996; 84: 321–330.

    CAS  Google Scholar 

  145. Wang Q, Stacy T, Binder M, Marin-Padilla M, Sharpe AH, Speck NA . Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Proc Natl Acad Sci USA 1996; 93: 3444–3449.

    CAS  Google Scholar 

  146. Okada H, Watanabe T, Niki M, Takano H, Chiba N, Yanai N et al. AML1(-/-) embryos do not express certain hematopoiesis-related gene transcripts including those of the PU.1 gene. Oncogene 1998; 17: 2287–2293.

    CAS  Google Scholar 

  147. De Braekeleer E, Douet-Guilbert N, Morel F, Le Bris MJ, Férec C, De Braekeleer M . RUNX1 translocations and fusion genes in malignant hemopathies. Future Oncol 2011; 7: 77–91.

    CAS  Google Scholar 

  148. Osato M . Point mutations in the RUNX1/AML1 gene: another actor in RUNX leukemia. Oncogene 2004; 23: 4284–4296.

    CAS  Google Scholar 

  149. Higuchi M, O'Brien D, Kumaravelu P, Lenny N, Yeoh EJ, Downing JR . Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia. Cancer Cell 2002; 1: 63–74.

    CAS  Google Scholar 

  150. Watanabe-Okochi N, Kitaura J, Ono R, Harada H, Harada Y, Komeno Y et al. AML1 mutations induced MDS and MDS/AML in a mouse BMT model. Blood 2008; 111: 4297–4308.

    CAS  Google Scholar 

  151. Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 1999; 23: 166–175.

    CAS  Google Scholar 

  152. 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: 1474–1481.

    CAS  Google Scholar 

  153. Niimi H, Harada H, Harada Y, Ding Y, Imagawa J, Inaba T et al. Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations. Leukemia 2006; 20: 635–644.

    CAS  Google Scholar 

  154. Chen CY, Lin LI, Tang JL, Ko BS, Tsay W, Chou WC et al. 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 2007; 139: 405–414.

    CAS  Google Scholar 

  155. Migas A, Savva N, Mishkova O, Aleinikova OV . AML1/RUNX1 gene point mutations in childhood myeloid malignancies. Pediatr Blood Cancer 2011; 57: 583–587.

    Google Scholar 

  156. Gaidzik VI, Bullinger L, Schlenk RF, Zimmermann AS, Röck J, Paschka P et al. RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group. J Clin Oncol 2011; 29: 1364–1372.

    Google Scholar 

  157. Neubauer A, Shannon K, Liu E . Mutations of the ras proto-oncogenes in childhood monosomy 7. Blood 1991; 77: 594–598.

    CAS  Google Scholar 

  158. Side LE, Curtiss NP, Teel K, Kratz C, Wang PW, Larson RA et al. RAS, FLT3, and TP53 mutations in therapy-related myeloid malignancies with abnormalities of chromosomes 5 and 7. Genes Chromosomes Cancer 2004; 39: 217–223.

    CAS  Google Scholar 

  159. Roumier C, Lejeune-Dumoulin S, Renneville A, Goethgeluck AS, Philipp N, Fenaux P et al. Cooperation of activating Ras/rtk signal transduction pathway mutations and inactivating myeloid differentiation gene mutations in M0 AML: a study of 45 patients. Leukemia 2006; 20: 433–436.

    CAS  Google Scholar 

  160. Rücker FG, Schlenk RF, Bullinger L, Kayser S, Teleanu V, Kett H et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood 2012; 119: 2114–2121.

    Google Scholar 

  161. 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: 148–150.

    CAS  Google Scholar 

  162. Loh ML, Vattikuti S, Schubbert S, Reynolds MG, Carlson E, Lieuw KH et al. Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood 2004; 103: 2325–2331.

    CAS  Google Scholar 

  163. Christiansen DH, Desta F, Andersen MK, Pedersen-Bjergaard J . Mutations of the PTPN11 gene in therapy-related MDS and AML with rare balanced chromosome translocations. Genes Chromosomes Cancer 2007; 46: 517–521.

    CAS  Google Scholar 

  164. Cristóbal 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: 615–625.

    Google Scholar 

  165. 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: 1401–1403.

    CAS  Google Scholar 

  166. Meggendorfer M, Bacher U, Alpermann T, Haferlach C, Kern W, Gambacorti-Passerini C et al. SETBP1 mutations occur in 9% of MDS/MPN and in 4% of MPN cases and are strongly associated with atypical CML, monosomy 7, isochromosome i(17)(q10), ASXL1 and CBL mutations. Leukemia 2013; 27: 1852–1860.

    CAS  Google Scholar 

  167. Hou HA, Kuo YY, Tang JL, Chou WC, Yao M, Lai YJ et al. Clinical implications of the SETBP1 mutation in patients with primary myelodysplastic syndrome and its stability during disease progression. Am J Hematol 2014; 89: 181–186.

    CAS  Google Scholar 

  168. 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.

    CAS  Google Scholar 

  169. Baranger L, Baruchel A, Leverger G, Schaison G, Berger R . Monosomy-7 in childhood hemopoietic disorders. Leukemia 1990; 4: 345–349.

    CAS  Google Scholar 

  170. Neukirchen J, Lauseker M, Blum S, Giagounidis A, Lübbert M, Martino S et al. Validation of the revised international prognostic scoring system (IPSS-R) in patients with myelodysplastic syndrome: a multicenter study. Leuk Res 2014; 38: 57–64.

    Google Scholar 

  171. Passmore SJ, Hann IM, Stiller CA, Ramani P, Swansbury GJ, Gibbons B et al. Pediatric myelodysplasia: a study of 68 children and a new prognostic scoring system. Blood 1995; 85: 1742–1750.

    CAS  Google Scholar 

  172. Kardos G, Baumann I, Passmore SJ, Locatelli F, Hasle H, Schultz KR et al. Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7. Blood 2003; 102: 1997–2003.

    CAS  Google Scholar 

  173. Trobaugh-Lotrario AD, Kletzel M, Quinones RR, McGavran L, Proytcheva MA, Hunger SP et al. Monosomy 7 associated with pediatric acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS): successful management by allogeneic hematopoietic stem cell transplant (HSCT). Bone Marrow Transplant 2005; 35: 143–149.

    CAS  Google Scholar 

  174. Madureira AB, Eapen M, Locatelli F, Teira P, Zhang MJ, Davies SM et al. Analysis of risk factors influencing outcome in children with myelodysplastic syndrome after unrelated cord blood transplantation. Leukemia 2011; 25: 449–454.

    CAS  Google Scholar 

  175. Webb DK, Passmore SJ, Hann IM, Harrison G, Wheatley K, Chessells JM . Results of treatment of children with refractory anaemia with excess blasts (RAEB) and RAEB in transformation (RAEBt) in Great Britain 1990-99. Br J Haematol 2002; 117: 33–39.

    Google Scholar 

  176. Yoshimi A, Strahm B, Baumann I, Furlan I, Schwarz S, Teigler-Schlegel A et al. Hematopoietic stem cell transplantation in children and young adults with secondary myelodysplastic syndrome and acute myelogenous leukemia after aplastic anemia. Biol Blood Marrow Transplant 2014; 20: 425–429.

    Google Scholar 

  177. Locatelli F, Crotta A, Ruggeri A, Eapen M, Wagner JE, Macmillan ML et al. Analysis of risk factors influencing outcomes after cord blood transplantation in children with juvenile myelomonocytic leukemia: a EUROCORD, EBMT, EWOG-MDS, CIBMTR study. Blood 2013; 122: 2135–2141.

    CAS  Google Scholar 

  178. Steele M, Hitzler J, Doyle JJ, Germeshausen M, Fernandez CV, Yuille K et al. Reduced intensity hematopoietic stem-cell transplantation across human leukocyte antigen barriers in a patient with congenital amegakaryocytic thrombocytopenia and monosomy 7. Pediatr Blood Cancer 2005; 45: 212–216.

    Google Scholar 

  179. Evans JP, Czepulkowski B, Gibbons B, Swansbury GJ, Chessells JM . Childhood monosomy 7 revisited. Br J Haematol 1988; 69: 4–5.

    Google Scholar 

  180. Hellström-Lindberg E, Robèrt KH, Gahrton G, Lindberg G, Forsblom AM, Kock Y et al. A predictive model for the clinical response to low dose ara-C: a study of 102 patients with myelodysplastic syndromes or acute leukaemia. Br J Haematol 1992; 81: 503–511.

    Google Scholar 

  181. Claus R, Lübbert M . Epigenetic targets in hematopoietic malignancies. Oncogene 2003; 22: 6489–6496.

    CAS  Google Scholar 

  182. Itzykson R, Fenaux P . Epigenetics of myelodysplastic syndromes. Leukemia 2014; 28: 497–506.

    CAS  Google Scholar 

  183. Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 2006; 106: 1794–1803.

    CAS  Google Scholar 

  184. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009; 10: 223–232.

    CAS  Google Scholar 

  185. Fenaux P, Gattermann N, Seymour JF, Hellström-Lindberg E, Mufti GJ, Duehrsen U et al. Prolonged survival with improved tolerability in higher-risk myelodysplastic syndromes: azacitidine compared with low dose ara-C. Br J Haematol 2010; 149: 244–249.

    CAS  Google Scholar 

  186. Lübbert M, Suciu S, Baila L, Rüter BH, Platzbecker U, Giagounidis A et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol 2011; 29: 1987–1996.

    Google Scholar 

  187. Hackanson B, Robbel C, Wijermans P, Lübbert M . In vivo effects of decitabine in myelodysplasia and acute myeloid leukemia: review of cytogenetic and molecular studies. Ann Hematol 2005; 84 (suppl 1): 32–38.

    CAS  Google Scholar 

  188. Raj KK, John AM, Ho A, Thomas NSB, Mufti GJ . Early and sustained response to azacytidine in high-risk MDS patients with monosomy 7 correlates with increased apoptosis and not CDKN2B demethylation. Blood 2005; 106 (suppl 1): 2530a.

    Google Scholar 

  189. Rüter B, Wijermans P, Claus R, Kunzmann R, Lübbert M . Preferential cytogenetic response to continuous intravenous low-dose decitabine (DAC) administration in myelodysplastic syndrome with monosomy 7. Blood 2007; 110: 1080–1082.

    Google Scholar 

  190. Raj K, John A, Ho A, Chronis C, Khan S, Samuel J et al. CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine. Leukemia 2007; 21: 1937–1944.

    CAS  Google Scholar 

  191. Daskalakis M, Nguyen TT, Nguyen C, Guldberg P, Köhler G, Wijermans P et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2'-deoxycytidine (decitabine) treatment. Blood 2002; 100: 2957–2964.

    CAS  Google Scholar 

  192. Gore SD, Baylin S, Sugar E, Carraway H, Miller CB, Carducci M et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res 2006; 66: 6361–6369.

    CAS  Google Scholar 

  193. Kantarjian H, Oki Y, Garcia-Manero G, Huang X, O’Brien S, Cortes J et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 2007; 109: 52–57.

    CAS  Google Scholar 

  194. Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, Yang H, Rosner G, Verstovsek S et al. Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia. Blood 2006; 108: 3271–3279.

    CAS  Google Scholar 

  195. Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F et al. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood 2007; 110: 2302–2308.

    CAS  Google Scholar 

  196. Griffiths EA, Gore SD . Epigenetic therapies in MDS and AML. Adv Exp Med Biol 2013; 754: 253–283.

    CAS  Google Scholar 

  197. Klco JM, Spencer DH, Lamprecht TL, Sarkaria SM, Wylie T, Magrini V et al. Genomic impact of transient low-dose decitabine treatment on primary AML cells. Blood 2013; 121: 1633–1643.

    CAS  Google Scholar 

  198. Hirayama Y, Sakamaki S, Tsuji Y, Sagawa T, Matsunaga T, Kato J et al. Recovery of cells with a normal karyotype in a refractory anaemia patient with monosomy 7-positive cells after long-term administration of cyclosporin A. Br J Haematol 2003; 121: 376–377.

    Google Scholar 

  199. Nagasawa M, Tomizawa D, Tsuji Y, Kajiwara M, Morio T, Nonoyama S et al. Pancytopenia presenting with monosomy 7 which disappeared after immunosuppressive therapy. Leuk Res 2004; 28: 315–319.

    Google Scholar 

  200. Hasegawa D, Manabe A, Yagasaki H, Ohtsuka Y, Inoue M, Kikuchi A et al. Treatment of children with refractory anemia: the Japanese Childhood MDS Study Group trial (MDS99). Pediatr Blood Cancer 2009; 53: 1011–1015.

    Google Scholar 

  201. Olnes MJ, Shenoy A, Weinstein B, Pfannes L, Loeliger K, Tucker Z et al. Directed therapy for patients with myelodysplastic syndromes (MDS) by suppression of cyclin D1 with ON 01910.Na. Leuk Res 2012; 36: 982–989.

    CAS  Google Scholar 

  202. Seetharam M, Fan AC, Tran M, Xu L, Renschler JP, Felsher DW et al. Treatment of higher risk myelodysplastic syndrome patients unresponsive to hypomethylating agents with ON 01910.Na. Leuk Res 2012; 36: 98–103.

    CAS  Google Scholar 

  203. Barreyro L, Will B, Bartholdy B, Zhou L, Todorova TI, Stanley RF et al. Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS. Blood 2012; 120: 1290–1298.

    CAS  Google Scholar 

  204. Rambaldi A, Torcia M, Bettoni S, Vannier E, Barbui T, Shaw AR et al. Modulation of cell proliferation and cytokine production in acute myeloblastic leukemia by interleukin-1 receptor antagonist and lack of its expression by leukemic cells. Blood 1991; 78: 3248–3253.

    CAS  Google Scholar 

  205. Dinarello CA . Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 2011; 117: 3720–3732.

    CAS  Google Scholar 

  206. Dawson MA, Prinjha RK, Dittmann A, Giotopoulos G, Bantscheff M, Chan WI et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 2011; 478: 529–533.

    CAS  Google Scholar 

  207. Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 2011; 478: 524–528.

    CAS  Google Scholar 

  208. Cortes J, Kantarjian H . How I treat newly diagnosed chronic phase CML. Blood 2012; 120: 1390–1397.

    CAS  Google Scholar 

  209. O'Hare T, Zabriskie MS, Eiring AM, Deininger MW . Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat Rev Cancer 2012; 12: 513–526.

    CAS  Google Scholar 

  210. Bisen A, Claxton DF . Tyrosine kinase targeted treatment of chronic myelogenous leukemia and other myeloproliferative neoplasms. Adv Exp Med Biol 2013; 779: 179–196.

    Google Scholar 

  211. Zinzani PL . The many faces of marginal zone lymphoma. Hematology Am Soc Hematol Educ Program 2012; 2012: 426–432.

    Google Scholar 

  212. Czarnecka KH, Migdalska-Sęk M, Antczak A, Pastuszak-Lewandoska D, Kordiak J, Nawrot E et al. Allelic imbalance in 1p, 7q, 9p, 11p, 12q and 16q regions in non-small cell lung carcinoma and its clinical association: a pilot study. Mol Biol Rep 2013; 40: 6671–6684.

    CAS  Google Scholar 

  213. Hodge JC, Park PJ, Dreyfuss JM, Assil-Kishawi I, Somasundaram P, Semere LG et al. Identifying the molecular signature of the interstitial deletion 7q subgroup of uterine leiomyomata using a paired analysis. Genes Chromosomes Cancer 2009; 48: 865–885.

    CAS  Google Scholar 

  214. Xia JC, Weng DS, Li JT, Qin HD, Mai SJ, Feng BJ et al. Loss of heterozygosity analysis of a candidate gastric carcinoma tumor suppressor locus at 7q31. Cancer Genet Cytogenet 2006; 166: 166–172.

    CAS  Google Scholar 

  215. Knudson AGJ . Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971; 68: 820–823.

    Google Scholar 

  216. Boultwood J . CUX1 in leukemia: dosage matters. Blood 2013; 121: 869–871.

    CAS  Google Scholar 

  217. Largaespada DA . Haploinsufficiency for tumor suppression: the hazards of being single and living a long time. J Exp Med 2001; 193: F15–F18.

    CAS  Google Scholar 

  218. Santarosa M, Ashworth A . Haploinsufficiency for tumour suppressor genes: when you don't need to go all the way. Biochim Biophys Acta 2004; 1654: 105–122.

    CAS  Google Scholar 

  219. Payne SR, Kemp CJ . Tumor suppressor genetics. Carcinogenesis 2005; 26: 2013–2045.

    Google Scholar 

  220. Berger AH, Knudson AG, Pandolfi PP . A continuum model for tumour suppression. Nature 2011; 476: 163–169.

    CAS  Google Scholar 

  221. Ebert BL, Pretz J, Bosco J, Chang CY, Tamayo P, Galili N et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature 2008; 451: 335–339.

    CAS  Google Scholar 

  222. Boultwood J, Pellagatti A, McKenzie AN, Wainscoat JS . Advances in the 5q- syndrome. Blood 2010; 116: 5803–5811.

    CAS  Google Scholar 

  223. Ozaki Y, Matsui H, Asou H, Nagamachi A, Aki D, Honda H et al. Poly-ADP ribosylation of Miki by tankyrase-1 promotes centrosome maturation. Mol Cell 2012; 47: 694–703.

    CAS  Google Scholar 

  224. Wong JC, Zhang Y, Lieuw KH, Tran MT, Forgo E, Weinfurtner K et al. Use of chromosome engineering to model a segmental deletion of chromosome band 7q22 found in myeloid malignancies. Blood 2010; 115: 4524–4532.

    CAS  Google Scholar 

  225. Wang H, Yang H, Shivalila CS, Dawlaty MM, Cheng AW, Zhang F et al. One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell 2013; 153: 910–918.

    CAS  Google Scholar 

  226. Yang H, Wang H, Shivalila CS, Cheng AW, Shi L, Jaenisch R . One-step generation of mice carrying reporter and conditional alleles by CRISPR/Cas-mediated genome engineering. Cell 2013; 154: 1370–1379.

    CAS  Google Scholar 

  227. Lujambio A, Lowe SW . The microcosmos of cancer. Nature 2012; 482: 347–355.

    CAS  Google Scholar 

  228. Esteller M . Non-coding RNAs in human disease. Nat Rev Genet 2011; 12: 861–874.

    CAS  Google Scholar 

  229. Kunej T, Godnic I, Ferdin J, Horvat S, Dovc P, Calin GA . Epigenetic pregulation of microRNAs in cancer: an integrated review of literature. Mutat Res 2011; 717: 77–84.

    CAS  Google Scholar 

  230. Maestrini E, Pagnamenta AT, Lamb JA, Bacchelli E, Sykes NH, Sousa I et al. High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L–DOCK4 gene region in autism susceptibility. Mol Psychiatry 2010; 15: 954–968.

    CAS  Google Scholar 

  231. Alkelai A, Lupoli S, Greenbaum L, Kohn Y, Kanyas-Sarner K, Ben-Asher E et al. DOCK4 and CEACAM21 as novel schizophrenia candidate genes in the Jewish population. Int J Neuropsychopharmacol 2012; 15: 459–469.

    CAS  Google Scholar 

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Acknowledgements

This work was in part supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Honda, H., Nagamachi, A. & Inaba, T. −7/7q− syndrome in myeloid-lineage hematopoietic malignancies: attempts to understand this complex disease entity. Oncogene 34, 2413–2425 (2015). https://doi.org/10.1038/onc.2014.196

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