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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Potten CS . Stem Cells Academic Press: London 1997
Lemischka IR . Clonal, in vivo behavior of the totipotent hematopoietic stem cell Semin Immunol 1991 3: 349–355
Morrison SJ, Uchida N, Weissman IL . The biology of hematopoietic stem cells Annu Rev Cell Dev Biol 1995 11: 35–71
Robertson EJ . Using embryonic stem cells to introduce mutations into the mouse germ line Biol Reprod 1991 44: 238–245
Gage FH . Mammalian neural stem cells Science 2000 287: 1433–1438
Alison M, Sarraf C . Hepatic stem cells J Hepatol 1998 29: 676–682
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
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
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
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
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
Schiller GJ . Treatment of resistant disease Leukemia 1998 12: (Suppl. 1) S20–S24
Paietta E . Classical multidrug resistance in acute myeloid leukaemia Med Oncol 1997 14: 53–60
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
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
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
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
Hara T, Miyajima A . Function and signal transduction mediated by the interleukin 3 receptor system in hematopoiesis Stem Cells 1996 14: 605–618
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
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
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
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
Appelbaum FR . Antibody-targeted therapy for myeloid leukemia Semin Hematol 1999 36: 2–8
Maloney DG . Advances in immunotherapy of hematologic malignancies Curr Opin Hematol 1998 5: 237–243
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
Press OW . Radiolabeled antibody therapy of B-cell lymphomas Semin Oncol 1999 26: 58–65
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
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
Green AR . Transcription factors, translocations and haematological malignancies Blood Rev 1992 6: 118–124
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
Drexler HG, Meyer C, Quentmeier H . Effects of FLT3 ligand on proliferation and survival of myeloid leukemia cells Leuk Lymphoma 1999 33: 83–91
Drexler HG, Quentmeier H . Thrombopoietin: expression of its receptor MPL and proliferative effects on leukemic cells Leukemia 1996 10: 1405–1421
Matsumura I, Ikeda H, Kanakura Y . The effects of thrombopoietin on the growth of acute myeloblastic leukemia cells Leuk Lymphoma 1996 23: 533–538
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
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
Sikic BI . New approaches in cancer treatment Ann Oncol 1999 10: (Suppl 6) 149–153
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.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2401903
Keywords
This article is cited by
-
TMIGD2 is an orchestrator and therapeutic target on human acute myeloid leukemia stem cells
Nature Communications (2024)
-
A blastic plasmacytoid dendritic cell neoplasm-like immunophenotype is negatively associated with CEBPA bZIP mutation and predicts unfavorable prognosis in acute myeloid leukemia
Annals of Hematology (2024)
-
Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123
Nature Biotechnology (2023)
-
Allogeneic TCRαβ deficient CAR T-cells targeting CD123 in acute myeloid leukemia
Nature Communications (2022)