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CD123 in Acute Myeloid Leukemia

The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells

Abstract

Recent studies suggest that the population of malignant cells found in human acute myelogenous leukemia (AML) arises from a rare population of leukemic stem cells (LSCs). LSCs have been documented for nearly all AML subtypes and have been phenotypically described as CD34+/CD38 or CD34+/HLA-DR. Given the potentially critical role of these primitive cells in perpetuating leukemic disease, we sought to further investigate their molecular and cellular characteristics. Flow cytometric studies using primary AML tissue showed that the interleukin-3 receptor alpha chain (IL-3Rα or CD123) was strongly expressed in CD34+/CD38 cells (98 ± 2% positive) from 16 of 18 primary specimens. Conversely, normal bone marrow derived CD34+/CD38 cells showed virtually no detectable expression of the CD123 antigen. To assess the functional role of IL-3Rα positive cells, purified CD34+/CD123+ leukemia cells were transplanted into immune deficient NOD/SCID mice. These experiments showed that CD123+ cells were competent to establish and maintain leukemic populations in vivo. To begin to elucidate a biological role for CD123 in leukemia, primary AML samples were analyzed with respect to signal transduction activity in the MAPK, Akt, and Stat5 pathways. Phosphorylation was not detected in response to IL-3 stimulation, thereby suggesting CD123 is not active in conventional IL-3-mediated signaling. Collectively, these data indicate that CD123 represents a unique marker for primitive leukemic stem cells. Given the strong expression of this receptor on LSCs, we propose that targeting of CD123 may be a promising strategy for the preferential ablation of AML cells.

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References

  1. Potten CS . Stem Cells Academic Press: London 1997

  2. Lemischka IR . Clonal, in vivo behavior of the totipotent hematopoietic stem cell Semin Immunol 1991 3: 349–355

    CAS  PubMed  Google Scholar 

  3. Morrison SJ, Uchida N, Weissman IL . The biology of hematopoietic stem cells Annu Rev Cell Dev Biol 1995 11: 35–71

    Article  CAS  PubMed  Google Scholar 

  4. Robertson EJ . Using embryonic stem cells to introduce mutations into the mouse germ line Biol Reprod 1991 44: 238–245

    Article  CAS  PubMed  Google Scholar 

  5. Gage FH . Mammalian neural stem cells Science 2000 287: 1433–1438

    Article  CAS  PubMed  Google Scholar 

  6. Alison M, Sarraf C . Hepatic stem cells J Hepatol 1998 29: 676–682

    Article  CAS  PubMed  Google Scholar 

  7. Bonnet D, Dick JE . Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell Nat Med 1997 3: 730–737

    Article  CAS  PubMed  Google Scholar 

  8. Blair A, Hogge DE, Sutherland HJ . Most acute myeloid leukemia progenitor cells with long-term proliferative ability in vitro and in vivo have the phenotype CD34(+)/CD71(−)/HLA-DR- Blood 1998 92: 4325–4335

    CAS  PubMed  Google Scholar 

  9. Cobaleda C, Gutierrez-Cianca N, Perez-Losada J, Flores T, Garcia-Sanz R, Gonzalez M, Sanchez-Garcia I . A primitive hematopoietic cell is the target for the leukemic transformation in human philadelphia-positive acute lymphoblastic leukemia Blood 2000 95: 1007–1013

    CAS  PubMed  Google Scholar 

  10. Blair A, Hogge DE, Ailles LE, Lansdorp PM, Sutherland HJ . Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo Blood 1997 89: 3104–3112

    CAS  PubMed  Google Scholar 

  11. Terpstra W, Ploemacher RE, Prins A, van Lom K, Pouwels K, Wognum AW, Wagemaker G, Lowenberg B, Wielenga JJ . Fluorouracil selectively spares acute myeloid leukemia cells with long-term growth abilities in immunodeficient mice and in culture Blood 1996 88: 1944–1950

    CAS  PubMed  Google Scholar 

  12. Schiller GJ . Treatment of resistant disease Leukemia 1998 12: (Suppl. 1) S20–S24

    CAS  PubMed  Google Scholar 

  13. Paietta E . Classical multidrug resistance in acute myeloid leukaemia Med Oncol 1997 14: 53–60

    Article  CAS  PubMed  Google Scholar 

  14. Murayama T, Imoto S, Natazuka T, Chihara K, Matsui T . Proliferative reaction of myelogenous leukemia cells with cytokines G-CSF, GM-CSF, M-CSF, SCF and TPO Leuk Res 1998 22: 557–560

    Article  CAS  PubMed  Google Scholar 

  15. Smith MA, Smith JG, Pallister CJ, Singer CR . Haemopoietic growth factors, the cell cycle of acute myeloblastic leukaemia progenitors and sensitivity to cytosine arabinoside Leuk Lymphoma 1996 23: 467–472

    Article  CAS  PubMed  Google Scholar 

  16. Ailles LE, Gerhard B, Hogge DE . Detection and characterization of primitive malignant and normal progenitors in patients with acute myelogenous leukemia using long-term coculture with supportive feeder layers and cytokines Blood 1997 90: 2555–2564

    CAS  PubMed  Google Scholar 

  17. Sato N, Caux C, Kitamura T, Watanabe Y, Arai K, Banchereau J, Miyajima A . Expression and factor-dependent modulation of the interleukin-3 receptor subunits on human hematopoietic cells Blood 1993 82: 752–761

    CAS  PubMed  Google Scholar 

  18. Hara T, Miyajima A . Function and signal transduction mediated by the interleukin 3 receptor system in hematopoiesis Stem Cells 1996 14: 605–618

    Article  CAS  PubMed  Google Scholar 

  19. Songyang Z, Baltimore D, Cantley LC, Kaplan DR, Franke TF . Interleukin 3-dependent survival by the Akt protein kinase Proc Natl Acad Sci USA 1997 94: 11345–11350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yagisawa M, Saeki K, Okuma E, Kitamura T, Kitagawa S, Hirai H, Yazaki Y, Takaku F, Yuo A . Signal transduction pathways in normal human monocytes stimulated by cytokines and mediators: comparative study with normal human neutrophils or transformed cells and the putative roles in functionality and cell biology Exp Hematol 1999 27: 1063–1076

    Article  CAS  PubMed  Google Scholar 

  21. Sutor SL, Vroman BT, Armstrong EA, Abraham RT, Karnitz LM . A phosphatidylinositol 3-kinase-dependent pathway that differentially regulates c-Raf and A-Raf J Biol Chem 1999 274: 7002–7010

    Article  CAS  PubMed  Google Scholar 

  22. de Groot RP, Coffer PJ, Koenderman L . Regulation of proliferation, differentiation and survival by the IL-3/IL-5/GM-CSF receptor family Cell Signal 1998 10: 619–628

    Article  CAS  PubMed  Google Scholar 

  23. Appelbaum FR . Antibody-targeted therapy for myeloid leukemia Semin Hematol 1999 36: 2–8

    CAS  PubMed  Google Scholar 

  24. Maloney DG . Advances in immunotherapy of hematologic malignancies Curr Opin Hematol 1998 5: 237–243

    Article  CAS  PubMed  Google Scholar 

  25. Grillo-Lopez AJ, White CA, Varns C, Shen D, Wei A, McClure A, Dallaire BK . Overview of the clinical development of rituximab: first monoclonal antibody approved for the treatment of lymphoma Semin Oncol 1999 26: 66–73

    CAS  PubMed  Google Scholar 

  26. Press OW . Radiolabeled antibody therapy of B-cell lymphomas Semin Oncol 1999 26: 58–65

    CAS  PubMed  Google Scholar 

  27. Bernstein ID . Monoclonal antibodies to the myeloid stem cells: therapeutic implications of CMA-676, a humanized anti-CD33 antibody calicheamicin conjugate Leukemia 2000 14: 474–475

    Article  CAS  PubMed  Google Scholar 

  28. Holyoake T, Jiang X, Eaves C, Eaves A . Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia Blood 1999 94: 2056–2064

    CAS  PubMed  Google Scholar 

  29. Green AR . Transcription factors, translocations and haematological malignancies Blood Rev 1992 6: 118–124

    Article  CAS  PubMed  Google Scholar 

  30. Strout MP, Marcucci G, Caligiuri MA, Bloomfield CD . Core-binding factor (CBF) and MLL-associated primary acute myeloid leukemia: biology and clinical implications Ann Hematol 1999 78: 251–264

    Article  CAS  PubMed  Google Scholar 

  31. Drexler HG, Meyer C, Quentmeier H . Effects of FLT3 ligand on proliferation and survival of myeloid leukemia cells Leuk Lymphoma 1999 33: 83–91

    Article  CAS  PubMed  Google Scholar 

  32. Drexler HG, Quentmeier H . Thrombopoietin: expression of its receptor MPL and proliferative effects on leukemic cells Leukemia 1996 10: 1405–1421

    CAS  PubMed  Google Scholar 

  33. Matsumura I, Ikeda H, Kanakura Y . The effects of thrombopoietin on the growth of acute myeloblastic leukemia cells Leuk Lymphoma 1996 23: 533–538

    Article  CAS  PubMed  Google Scholar 

  34. Jiang X, Lopez A, Holyoake T, Eaves A, Eaves C . Autocrine production and action of IL-3 and granulocyte colony-stimulating factor in chronic myeloid leukemia Proc Natl Acad Sci USA 1999 96: 12804–12809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Korpelainen EI, Gamble JR, Smith WB, Dottore M, Vadas MA, Lopez AF . Interferon-gamma upregulates interleukin-3 (IL-3) receptor expression in human endothelial cells and synergizes with IL-3 in stimulating major histocompatibility complex class II expression and cytokine production Blood 1995 86: 176–182

    CAS  PubMed  Google Scholar 

  36. Sikic BI . New approaches in cancer treatment Ann Oncol 1999 10: (Suppl 6) 149–153

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants to CTJ from the Leukemia and Lymphoma Society (translational grant 6057–99), and the American Cancer Society (grant RPG-99-206-01-LBC). SJS is supported by a Junior Faculty Award from the American Society of Hematology. We gratefully acknowledge the generous support of the McDowell Cancer Foundation and the Donatina Colachicco Cancer Research Fund. We also thank Drs Gary Van Zant and E Charles Snow for helpful discussions and critical evaluation of the manuscript. Further, we acknowledge the National Disease Research Interchange (NDRI) for help in procuring normal bone marrow specimens.

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Jordan, C., Upchurch, D., Szilvassy, S. et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia 14, 1777–1784 (2000). https://doi.org/10.1038/sj.leu.2401903

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