Experimental Hematology
Volume 35, Issue 3 , Pages 394-406 , March 2007

Loss of the tumor suppressor p15Ink4b enhances myeloid progenitor formation from common myeloid progenitors

Received 11 August 2006 ,Revised 6 November 2006 ,Accepted 8 November 2006.

References 

  1. Ogawa M. Hematopoiesis. J Allergy Clin Immunol. 1994;94:645–650
  2. Shizuru JA, Negrin RS, Weissman IL. Hematopoietic stem and progenitor cells: clinical and preclinical regeneration of the hematolymphoid system. Annu Rev Med. 2005;56:509–538
  3. Morrison SJ, Uchida N, Weissman IL. The biology of hematopoietic stem cells. Annu Rev Cell Dev Biol. 1995;11:35–71
  4. Ogawa M. Differentiation and proliferation of hematopoietic stem cells. Blood. 1993;81:2844–2853
  5. Warner JK, Wang JC, Hope KJ, Jin L, Dick JE. Concepts of human leukemic development. Oncogene. 2004;23:7164–7177
  6. Pardee AB. G1 events and regulation of cell proliferation. Science. 1989;246:603–608
  7. Ekholm SV, Reed SI. Regulation of G(1) cyclin-dependent kinases in the mammalian cell cycle. Curr Opin Cell Biol. 2000;12:676–684
  8. Ruas M, Peters G. The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim Biophys Acta. 1998;1378:F115–F177
  9. Yuan Y, Shen H, Franklin DS, Scadden DT, Cheng T. In vivo self-renewing divisions of haematopoietic stem cells are increased in the absence of the early G1-phase inhibitor, p18INK4C. Nat Cell Biol. 2004;6:436–442
  10. Ito K, Hirao A, Arai F, et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature. 2004;431:997–1002
  11. Krug U, Ganser A, Koeffler HP. Tumor suppressor genes in normal and malignant hematopoiesis. Oncogene. 2002;21:3475–3495
  12. Cameron EE, Baylin SB, Herman JG. p15INK4B CpG island methylation in primary acute leukemia is heterogeneous and suggests density as a critical factor for transcriptional silencing. Blood. 1999;94:2445–2451
  13. Teofili L, Martini M, Luongo M, et al. Hypermethylation of GpG islands in the promoter region of p15(INK4b) in acute promyelocytic leukemia represses p15(INK4b) expression and correlates with poor prognosis. Leukemia. 2003;17:919–924
  14. Herman JG, Jen J, Merlo A, Baylin SB. Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. Cancer Res. 1996;56:722–727
  15. Wolff L, Garin MT, Koller R, et al. Hypermethylation of the Ink4b locus in murine myeloid leukemia and increased susceptibility to leukemia in p15(Ink4b)-deficient mice. Oncogene. 2003;22:9265–9274
  16. Aoki E, Uchida T, Ohashi H, et al. Methylation status of the p15INK4B gene in hematopoietic progenitors and peripheral blood cells in myelodysplastic syndromes. Leukemia. 2000;14:586–593
  17. Uchida T, Kinoshita T, Nagai H, et al. Hypermethylation of the p15INK4B gene in myelodysplastic syndromes. Blood. 1997;90:1403–1409
  18. Aggerholm A, Holm MS, Guldberg P, Olesen LH, Hokland P. Promoter hypermethylation of p15INK4B, HIC1, CDH1, and ER is frequent in myelodysplastic syndrome and predicts poor prognosis in early-stage patients. Eur J Haematol. 2006;76:23–32
  19. Latres E, Malumbres M, Sotillo R, et al. Limited overlapping roles of P15INK4b and P18INK4c cell cycle inhibitors in proliferation and tumorigenesis. EMBO J. 2000;19:3496–3506
  20. Christensen JL, Weissman IL. Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc Natl Acad Sci U S A. 2001;98:14541–14546
  21. Akashi K, Traver D, Miyamoto T, Weissman IL. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature. 2000;404:193–197
  22. Nutt SL, Metcalf D, D'Amico A, Polli M, Wu L. Dynamic regulation of PU.1 expression in multipotent hematopoietic progenitors. J Exp Med. 2005;201:221–231
  23. Fleming TJ, Fleming ML, Malek TR. Selective expression of Ly-6G on myeloid lineage cells in mouse bone marrow. RB6-8C5 mAb to granulocyte-differentiation antigen (Gr-1) detects members of the Ly-6 family. J Immunol. 1993;151:2399–2408
  24. Kondo M, Weissman IL, Akashi K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell. 1997;91:661–672
  25. Ikuta K, Weissman IL. Evidence that hematopoietic stem cells express mouse c-kit but do not depend on steel factor for their generation. Proc Natl Acad Sci U S A. 1992;89:1502–1506
  26. Cozzio A, Passegue E, Ayton PM, Karsunky H, Cleary ML, Weissman IL. Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev. 2003;17:3029–3035
  27. Bedi A, Sharkis SJ. Mechanisms of cell commitment in myeloid cell differentiation. Curr Opin Hematol. 1995;2:12–21
  28. Keller JR, Ortiz M, Ruscetti FW. Steel factor (c-kit ligand) promotes the survival of hematopoietic stem/progenitor cells in the absence of cell division. Blood. 1995;86:1757–1764
  29. Domen J, Weissman IL. Hematopoietic stem cells need two signals to prevent apoptosis; BCL-2 can provide one of these, Kitl/c-Kit signaling the other. J Exp Med. 2000;192:1707–1718
  30. Andree HA, Reutelingsperger CP, Hauptmann R, Hemker HC, Hermens WT, Willems GM. Binding of vascular anticoagulant alpha (VAC alpha) to planar phospholipid bilayers. J Biol Chem. 1990;265:4923–4928
  31. van EM, Nieland LJ, Ramaekers FC, Schutte B, Reutelingsperger CP. Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry. 1998;31:1–9
  32. Cheng T, Rodrigues N, Dombkowski D, Stier S, Scadden DT. Stem cell repopulation efficiency but not pool size is governed by p27(kip1). Nat Med. 2000;6:1235–1240
  33. Cheng T, Rodrigues N, Shen H, et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science. 2000;287:1804–1808
  34. Greenberg PL, Young NS, Gattermann N. Myelodysplastic syndromes. Hematology (Am Soc Hematol Educ Program). 2002;136–161
  35. Hofmann WK, Takeuchi S, Takeuchi N, Thiel E, Hoelzer D, Koeffler HP. Comparative analysis of hypermethylation of cell cycle control and DNA-mismatch repair genes in low-density and CD34+ bone marrow cells from patients with myelodysplastic syndrome. Leuk Res. 2006;30:1347–1353
  36. Quesnel B. Methylation and myelodysplastic syndromes: when and where?. Leuk Res. 2006;30:1327–1329
  37. Teofili L, Martini M, Di MA, et al. Expression of p15(ink4b) gene during megakaryocytic differentiation of normal and myelodysplastic hematopoietic progenitors. Blood. 2001;98:495–497
  38. Teofili L, Rutella S, Chiusolo P, et al. Expression of p15INK4B in normal hematopoiesis. Exp Hematol. 1998;26:1133–1139
  39. Guo Y, Engelhardt M, Wider D, Abdelkarim M, Lubbert M. Effects of 5-aza-2′-deoxycytidine on proliferation, differentiation and p15/INK4b regulation of human hematopoietic progenitor cells. Leukemia. 2006;20:115–121
  40. Amanullah A, Hoffman B, Liebermann DA. Deregulated E2F-1 blocks terminal differentiation and loss of leukemogenicity of M1 myeloblastic leukemia cells without abrogating induction of p15(INK4B) and p16(INK4A). Blood. 2000;96:475–482
  41. Schmidt M, Bies J, Tamura T, Ozato K, Wolff L. The interferon regulatory factor ICSBP/IRF-8 in combination with PU.1 up-regulates expression of tumor suppressor p15(Ink4b) in murine myeloid cells. Blood. 2004;103:4142–4149
  42. Schmidt M, Koller R, Haviernik P, Bies J, Maciag K, Wolff L. Deregulated c-Myb expression in murine myeloid leukemias prevents the up-regulation of p15(INK4b) normally associated with differentiation. Oncogene. 2001;20:6205–6214
  43. Jamieson CH, Ailles LE, Dylla SJ, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004;351:657–667
  44. Weissman I. Stem cell research: paths to cancer therapies and regenerative medicine. JAMA. 2005;294:1359–1366
  45. Wang J, Iwasaki H, Krivtsov A, et al. Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease. EMBO J. 2005;24:368–381

PII: S0301-472X(06)00699-0

doi: 10.1016/j.exphem.2006.11.005

Experimental Hematology
Volume 35, Issue 3 , Pages 394-406 , March 2007