International Journal of Hematology

, Volume 94, Issue 2, pp 109–117 | Cite as

Self-renewal related signaling in myeloid leukemia stem cells

  • Florian H. Heidel
  • Brenton G. Mar
  • Scott A. Armstrong
Progress in Hematology Signaling and transcription in the development of leukemia


A key characteristic of hematopoietic stem cells (HSC) is the ability to self-renew. Several genes and signaling pathways control the fine balance between self-renewal and differentiation in HSC and potentially also in leukemic stem cells. Besides pathways such as Wnt signaling, Hedgehog signaling and Notch signaling, transcription factors (FoxOs) and cell fate determinants may also play a role in stem cells. While some of these pathways seem to be dispensable for maintenance of adult HSC, there may be a distinct requirement in leukemia stem cells for leukemic self-renewal. Here we will focus on self-renewal related signaling in myeloid leukemia stem cells and its therapeutic relevance.


Leukemia stem cell Self-renewal Hedgehog Wnt Notch FoxO 


  1. 1.
    Lapidot T, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367(6464):645–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol. 2004;5(7):738–43.CrossRefPubMedGoogle Scholar
  4. 4.
    Cozzio A, et al. Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev. 2003;17(24):3029–35.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Huntly BJ, et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell. 2004;6(6):587–96.CrossRefPubMedGoogle Scholar
  6. 6.
    Krivtsov AV, et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature. 2006;442(7104):818–22.CrossRefPubMedGoogle Scholar
  7. 7.
    Somervaille TC, Cleary ML. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell. 2006;10(4):257–68.CrossRefPubMedGoogle Scholar
  8. 8.
    Lowenberg B, et al. Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy—the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon Group. J Clin Oncol. 1998;16(3):872–81.CrossRefPubMedGoogle Scholar
  9. 9.
    Stone RM, et al. Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. N Engl J Med. 1995;332(25):1671–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Mayer RJ, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med. 1994;331(14):896–903.CrossRefPubMedGoogle Scholar
  11. 11.
    Cortes J, et al. Front-line and salvage therapies with tyrosine kinase inhibitors and other treatments in chronic myeloid leukemia. J Clin Oncol. 2011;29(5):524–31.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Mahon FX, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11(11):1029–35.CrossRefPubMedGoogle Scholar
  13. 13.
    Rousselot P, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood. 2007;109(1):58–60.CrossRefPubMedGoogle Scholar
  14. 14.
    Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001;15(23):3059–87.CrossRefPubMedGoogle Scholar
  15. 15.
    Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature. 1980;287(5785):795–801.CrossRefPubMedGoogle Scholar
  16. 16.
    Ahn S, Joyner AL. In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature. 2005;437(7060):894–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature. 2004;432(7015):324–31.CrossRefPubMedGoogle Scholar
  18. 18.
    Lee J, et al. Gli1 is a target of Sonic hedgehog that induces ventral neural tube development. Development. 1997;124(13):2537–52.PubMedGoogle Scholar
  19. 19.
    Ikram MS, et al. GLI2 is expressed in normal human epidermis and BCC and induces GLI1 expression by binding to its promoter. J Invest Dermatol. 2004;122(6):1503–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Teglund S, Toftgard R. Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim Biophys Acta. 2010;1805(2):181–208.PubMedGoogle Scholar
  21. 21.
    Zhang XM, Ramalho-Santos M, McMahon AP. Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R symmetry by the mouse node. Cell. 2001;106(2):781–92.CrossRefPubMedGoogle Scholar
  22. 22.
    Dierks C, et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell. 2008;14(3):238–49.CrossRefPubMedGoogle Scholar
  23. 23.
    Gao J, et al. Hedgehog signaling is dispensable for adult hematopoietic stem cell function. Cell Stem Cell. 2009;4(6):548–58.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Hofmann I, et al. Hedgehog signaling is dispensable for adult murine hematopoietic stem cell function and hematopoiesis. Cell Stem Cell. 2009;4(6):559–67.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Zhao C, et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature. 2009;458(7239):776–9.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Irvine DA, et al. Combination of Hedgehog pathway inhibitor LDE225 and Nilotinib eliminates chronic myeloid leukemia stem and progenitor cells. Blood (ASH). 2009 (abstract no. 1428).Google Scholar
  27. 27.
    Zhang B, et al. Inhibition of chronic myeloid leukemia stem cells by the combination of the Hoedgehog pathway inhibitor LDE225 with Nilotinib. Blood (ASH). 2010 (abstract no. 514).Google Scholar
  28. 28.
    Schairer A, et al. Human blast crisis leukemia stem cell inhibition with a novel smoothened antagonist. Blood (ASH). 2010 (abstract no. 1223).Google Scholar
  29. 29.
    Behrens J, et al. Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science. 1998;280(5363):596–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Rubinfeld B, et al. Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science. 1996;272(5264):1023–6.CrossRefPubMedGoogle Scholar
  31. 31.
    Tamai K, et al. LDL-receptor-related proteins in Wnt signal transduction. Nature. 2000;407(6803):530–5.CrossRefPubMedGoogle Scholar
  32. 32.
    Mao J, et al. Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell. 2001;7(4):801–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Mao B, et al. LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature. 2001;411(6835):321–5.CrossRefPubMedGoogle Scholar
  34. 34.
    Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science. 2004;303(5663):1483–7.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Haegel H, et al. Lack of beta-catenin affects mouse development at gastrulation. Development. 1995;121(11):3529–37.PubMedGoogle Scholar
  36. 36.
    Fleming HE, et al. Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell. 2008;2(3):274–83.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Zhao C, et al. Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell. 2007;12(6):528–41.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Koch U, et al. Simultaneous loss of beta- and gamma-catenin does not perturb hematopoiesis or lymphopoiesis. Blood. 2008;111(1):160–4.CrossRefPubMedGoogle Scholar
  39. 39.
    Hu Y, et al. beta-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia. Leukemia. 2009;23(1):109–16.CrossRefPubMedGoogle Scholar
  40. 40.
    Heidel FH, et al. Beta-catenin (Ctnnb1) suppression targets imatinib resistant leukemia stem cells in mice with BCR-ABL induced myeloproliferative disease. Blood (ASH). 2010 (annual meeting abstracts).Google Scholar
  41. 41.
    Jamieson CH, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004;351(7):657–67.CrossRefPubMedGoogle Scholar
  42. 42.
    Abrahamsson AE, et al. Glycogen synthase kinase 3beta missplicing contributes to leukemia stem cell generation. Proc Natl Acad Sci USA. 2009;106(10):3925–9.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Wang Y, et al. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010;327(5973):1650–3.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Yeung J, et al. beta-Catenin mediates the establishment and drug resistance of MLL leukemic stem cells. Cancer Cell. 2010;18(6):606–18.CrossRefPubMedGoogle Scholar
  45. 45.
    North TE, et al. Hematopoietic stem cell development is dependent on blood flow. Cell. 2009;137(4):736–48.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Goessling W, et al. Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration. Cell. 2009;136(6):1136–47.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Eaves CJ, Humphries RK. Acute myeloid leukemia and the Wnt pathway. N Engl J Med. 2010;362(24):2326–7.CrossRefPubMedGoogle Scholar
  48. 48.
    Tothova Z, Gilliland DG. FoxO transcription factors and stem cell homeostasis: insights from the hematopoietic system. Cell Stem Cell. 2007;1(2):140–52.CrossRefPubMedGoogle Scholar
  49. 49.
    Tothova Z, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell. 2007;128(2):325–39.CrossRefPubMedGoogle Scholar
  50. 50.
    Miyamoto K, et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell. 2007;1(1):101–12.CrossRefPubMedGoogle Scholar
  51. 51.
    Naka K, et al. TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature. 2010;463(7281):676–80.CrossRefPubMedGoogle Scholar
  52. 52.
    Sykes SM, et al. The AKT/FOXO signaling pathway is required for the maintenance of acute myeloid leukemia. Cell. 2011 (in press).Google Scholar
  53. 53.
    Duncan AW, et al. Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance. Nat Immunol. 2005;6(3):314–22.CrossRefPubMedGoogle Scholar
  54. 54.
    Wu M, et al. Imaging hematopoietic precursor division in real time. Cell Stem Cell. 2007;1(5):541–54.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Allman D, Aster JC, Pear WS. Notch signaling in hematopoiesis and early lymphocyte development. Immunol Rev. 2002;187:75–86.CrossRefPubMedGoogle Scholar
  56. 56.
    Artavanis-Tsakonas S, Matsuno K, Fortini ME. Notch signaling. Science. 1995;268(5208):225–32.CrossRefPubMedGoogle Scholar
  57. 57.
    Wu L, et al. MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nat Genet. 2000;26(4):484–9.CrossRefPubMedGoogle Scholar
  58. 58.
    Varnum-Finney B, et al. Immobilization of Notch ligand, Delta-1, is required for induction of notch signaling. J Cell Sci. 2000;113(Pt 23):4313–8.PubMedGoogle Scholar
  59. 59.
    Chen PM, et al. Down-regulation of Notch-1 expression decreases PU.1-mediated myeloid differentiation signaling in acute myeloid leukemia. Int J Oncol. 2008;32(6):1335–41.PubMedGoogle Scholar
  60. 60.
    Nakahara F, et al. Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia. Blood. 2010;115(14):2872–81.CrossRefPubMedGoogle Scholar
  61. 61.
    Klinakis A, et al. A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Nature. 2011;473(7346):230–3.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Hope KJ, et al. An RNAi screen identifies Msi2 and Prox1 as having opposite roles in the regulation of hematopoietic stem cell activity. Cell Stem Cell. 2010;7(1):101–13.CrossRefPubMedGoogle Scholar
  63. 63.
    Ito T, et al. Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature. 2010;466(7307):765–8.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Kharas MG, et al. Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia. Nat Med. 2010;16(8):903–8.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Okabe M, et al. Translational repression determines a neuronal potential in Drosophila asymmetric cell division. Nature. 2001;411(6833):94–8.CrossRefPubMedGoogle Scholar
  66. 66.
  67. 67.
    Gupta RA, Dubois RN. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer. 2001;1(1):11–21.CrossRefPubMedGoogle Scholar
  68. 68.
    Rothwell PM, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010;376(9754):1741–50.CrossRefPubMedGoogle Scholar
  69. 69.
    Rothwell PM, et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011;377(9759):31–41.CrossRefPubMedGoogle Scholar
  70. 70.
    Shah S, et al. Trans-repression of beta-catenin activity by nuclear receptors. J Biol Chem. 2003;278(48):48137–45.CrossRefPubMedGoogle Scholar
  71. 71.
    Jaiswal AS, et al. Beta-catenin-mediated transactivation and cell–cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene. 2002;21(55):8414–27.CrossRefPubMedGoogle Scholar
  72. 72.
    Roccaro AM, et al. Resveratrol exerts antiproliferative activity and induces apoptosis in Waldenstrom’s macroglobulinemia. Clin Cancer Res. 2008;14(6):1849–58.CrossRefPubMedGoogle Scholar
  73. 73.
    Takahashi-Yanaga F, Kahn M. Targeting Wnt signaling: can we safely eradicate cancer stem cells? Clin Cancer Res. 2010;16(12):3153–62.CrossRefPubMedGoogle Scholar
  74. 74.
    Huang SM, et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature. 2009;461(7264):614–20.CrossRefPubMedGoogle Scholar
  75. 75.
    You L, et al. An anti-Wnt-2 monoclonal antibody induces apoptosis in malignant melanoma cells and inhibits tumor growth. Cancer Res. 2004;64(15):5385–9.CrossRefPubMedGoogle Scholar
  76. 76.
    You L, et al. Inhibition of Wnt-1 signaling induces apoptosis in beta-catenin-deficient mesothelioma cells. Cancer Res. 2004;64(10):3474–8.CrossRefPubMedGoogle Scholar
  77. 77.
    DeAlmeida VI, et al. The soluble wnt receptor Frizzled8CRD-hFc inhibits the growth of teratocarcinomas in vivo. Cancer Res. 2007;67(11):5371–9.CrossRefPubMedGoogle Scholar
  78. 78.
    Hoey T, et al. DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell. 2009;5(2):168–77.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2011

Authors and Affiliations

  • Florian H. Heidel
    • 1
    • 2
    • 3
  • Brenton G. Mar
    • 1
    • 2
  • Scott A. Armstrong
    • 1
    • 2
    • 4
  1. 1.Division of Hematology/OncologyChildren’s HospitalBostonUSA
  2. 2.Department of Pediatric OncologyDana-Farber-Cancer Institute, Harvard Medical SchoolBostonUSA
  3. 3.Department of Hematology/OncologyOtto-von-Guericke University MagdeburgMagdeburgGermany
  4. 4.Harvard Stem Cell InstituteBostonUSA

Personalised recommendations