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A clonogenic common myeloid progenitor that gives rise to all myeloid lineages

Abstract

Haematopoietic stem cells give rise to progeny that progressively lose self-renewal capacity and become restricted to one lineage1,2. The points at which haematopoietic stem cell-derived progenitors commit to each of the various lineages remain mostly unknown. We have identified a clonogenic common lymphoid progenitor that can differentiate into T, B and natural killer cells but not myeloid cells3. Here we report the prospective identification, purification and characterization, using cell-surface markers and flow cytometry, of a complementary clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Common myeloid progenitors give rise to either megakaryocyte/erythrocyte or granulocyte/macrophage progenitors. Purified progenitors were used to provide a first-pass expression profile of various haematopoiesis-related genes. We propose that the common lymphoid progenitor and common myeloid progenitor populations reflect the earliest branch points between the lymphoid and myeloid lineages, and that the commitment of common myeloid progenitors to either the megakaryocyte/erythrocyte or the granulocyte/macrophage lineages are mutually exclusive events.

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Figure 1: Identification of myeloid progenitors in mouse bone marrow.
Figure 2: Morphology of day-7 colonies derived from sorted myeloid progenitors.
Figure 3: Lineage relationships among the myeloid progenitor subsets.
Figure 4: Differential expression of transcription factors in various stages of myeloid and lymphoid progenitors.
Figure 5: Proposed model of major haematopoietic maturation pathways from HSCs.

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References

  1. Dexter, T. M. Introduction to the haemopoietic system. Cancer Surv. 9, 1–5 (1990).

    CAS  PubMed  Google Scholar 

  2. Metcalf, D. Stem cells, pre-progenitor cells and lineage-committed cells: are our dogmas correct? Ann. NY Acad. Sci. 872, 289– 303 (1999).

    Article  ADS  CAS  PubMed  Google Scholar 

  3. Kondo, M., Weissman, I. L. & Akashi, K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91, 661– 672 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Akashi, K., Kondo, M., von Freeden-Jeffry, U., Murray, R. & Weissman, I. L. Bcl-2 rescues T lymphopoiesis in interleukin-7 receptor-deficient mice. Cell 89, 1033–1041 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Spangrude, G. J., Heimfeld, S. & Weissman, I. L. Purification and characterization of mouse hematopoietic stem cells. Science 241, 58– 62 (1988).

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Osawa, M., Hanada, K., Hamada, H. & Nakauchi, H. Long-term lymphohematopoietic reconstitution by a single CD34– low/negative hematopoietic stem cell. Science 273, 242–245 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Morrison, S. J. & Weissman, I. L. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1, 661– 673 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Lacaud, G., Carlsson, L. & Keller, G. Identification of a fetal hematopoietic precursor with B cell, T cell, and macrophage potential. Immunity 9, 827–838 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Ogawa, M. Differentiation and proliferation of hematopoietic stem cells. Blood 81, 2844–2853 ( 1993).

    CAS  PubMed  Google Scholar 

  10. Metcalf, D., Johnson, G. R. & Mandel, T. E. Colony formation in agar by multipotential hemopoietic cells. J. Cell Physiol. 98, 401– 420 (1979).

    Article  CAS  PubMed  Google Scholar 

  11. Morrison, S. J., Wandycz, A. M., Akashi, K., Globerson, A. & Weissman, I. L. The aging of hematopoietic stem cells. Nature Med. 2, 1011-6 ( 1996).

    PubMed  Google Scholar 

  12. Uchida, N., Aguila, H. L., Fleming, W. H., Jerabek, L. & Weissman, I. L. Rapid and sustained hematopoietic recovery in lethally irradiated mice transplanted with purified Thy-1. 1lo Lin–Sca-1+ hematopoietic stem cells. Blood 83 , 3758–3779 (1994).

    CAS  PubMed  Google Scholar 

  13. Domen, J., Gandy, K. L. & Weissman, I. L. Systemic overexpression of BCL-2 in the hematopoietic system protects transgenic mice from the consequences of lethal irradiation. Blood 91, 2272–2282 (1998).

    CAS  PubMed  Google Scholar 

  14. Pevny, L. et al. Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1. Nature 349, 257–260 (1991).

    Article  ADS  CAS  PubMed  Google Scholar 

  15. Fujiwara, Y., Browne, C. P., Cunniff, K., Goff, S. C. & Orkin, S. H. Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1. Proc. Natl Acad. Sci. USA 93, 12355– 12358 (1996).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shivdasani, R. A., Fujiwara, Y., McDevitt, M. A. & Orkin, S. H. A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development. EMBO J. 16, 3965–3973 ( 1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Shivdasani, R. A., Mayer, E. L. & Orkin, S. H. Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature 373, 432–434 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Tenen, D. G., Hromas, R., Licht, J. D. & Zhang, D. E. Transcription factors, normal myeloid development, and leukemia. Blood 90, 489–519 (1997).

    CAS  PubMed  Google Scholar 

  19. Nutt, S. L., Urbanek, P., Rolink, A. & Busslinger, M. Essential functions of Pax5 (BSAP) in pro-B cell development: difference between fetal and adult B lymphopoiesis and reduced V-to-DJ recombination at the IgH locus. Genes Dev. 11, 476–491 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  20. Morgan, B. et al. Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation. EMBO J. 16, 2004–2013 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ting, C. N., Olson, M. C., Barton, K. P. & Leiden, J. M. Transcription factor GATA-3 is required for development of the T-cell lineage. Nature 384, 474–478 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Hu, M. et al. Multilineage gene expression precedes commitment in the hemopoietic system. Genes Dev. 11, 774– 785 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Enver, T. & Greaves, M. Loops, lineage, and leukemia. Cell 94, 9–12 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  24. Miyamoto, T. et al. Persistence of multipotent progenitors expressing AML1/ETO transcripts in long-term remission patients with t(8;21) acute myelogenous leukemia. Blood 87, 4789– 4796 (1996).

    CAS  PubMed  Google Scholar 

  25. Weiss, M. J., Keller, G. & Orkin, S. H. Novel insights into erythroid development revealed through in vitro differentiation of GATA-1 embryonic stem cells. Genes Dev. 8, 1184–1197 ( 1994).

    Article  CAS  PubMed  Google Scholar 

  26. Robb, L. et al. Absence of yolk sac hematopoiesis from mice with a targeted disruption of the scl gene. Proc. Natl Acad. Sci. USA 92, 7075–7079 (1995).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  27. Landschulz, W. H., Johnson, P. F., Adashi, E. Y., Graves, B. J. & McKnight, S. L. Isolation of a recombinant copy of the gene encoding C/EBP. Genes Dev. 2, 786–800 (1988).

    Article  CAS  PubMed  Google Scholar 

  28. Ko, L. J. et al. Murine and human T-lymphocyte GATA-3 factors mediate transcription through a cis-regulatory element within the human T-cell receptor delta gene enhancer. Mol. Cell. Biol. 11, 2778 –2784 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Keller, G., Kennedy, M., Papayannopoulou, T. & Wiles, M. V. Hematopoietic commitment during embryonic stem cell differentiation in culture. Mol. Cell. Biol. 13, 473– 486 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Andrews, N. C., Erdjument-Bromage, H., Davidson, M. B., Tempst, P. & Orkin, S. H. Erythroid transcription factor NF-E2 is a haematopoietic-specific basic- leucine zipper protein. Nature 362, 722–728 ( 1993).

    Article  ADS  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by a USPHS US Public Health Service grant to I.L.W. and a 1997 Jose Carreras International Leukemia Foundation grant to K.A. D.T. is supported by a National Institute of Allergy and Infectious Diseases Training Grant. We thank S.-I. Nishikawa for anti-IL-7R antibody, J. Domen for H2K- BCL-2 mice and helpful discussions, D. Wright and A. Kiger for critical evaluation of the manuscript, L. Jerabek for excellent laboratory management and assistance with animal procedures, V. Braunstein for antibody preparation, the Stanford FACS facility for flow cytometer maintenance, and L. Hidalgo and B. Lavarro for animal care.

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Correspondence to Koichi Akashi.

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Akashi, K., Traver, D., Miyamoto, T. et al. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193–197 (2000). https://doi.org/10.1038/35004599

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