Mammalian myeloid progenitor cell subsets

Details Mammalian myeloid progenitor cell subsets Mammalian myeloid progenitor cell subsets

2000-06-29

2002-10-15

Saunders, David (Department: 1644)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

C424S093200, C424S093700, C435S002000, C435S354000, C435S355000, C435S372000

Reexamination Certificate

active

06465247

ABSTRACT:

BACKGROUND
The mammalian immune system plays a vital role in protection from disease, but its effectiveness rests on a fragile balance of power. Excessive or inappropriate responses result in autoimmune disease, while a failure to respond results in immunodeficiency. When such conditions occur, therapeutic intervention may be required. However, it is not easy to successfully manipulate such a complex system.
The mature cells of the immune system, T cells, B cells and natural killer cells, continually differentiate from hematopoietic stem cells, through a series of cell divisions. It is believed that after each cell division the developmental potential of the daughter cells is either maintained or further restricted relative to the parent, never expanded. One therefore observes that pluripotential stem cells give rise to multi-lineage committed progenitor cells, which give rise to specific lineages and finally mature cells. The coordinated changes of cellular properties leading to irreversible restriction of lineage commitment may be due to sequential activation or silencing of various genes.
The phenotype of long-lived pluripotential hematopoietic stem cells has been described. However, the identification of intermediate bipotent or oligopotent progenitors has been difficult, since the evaluation of differentiating potential may be perturbed by a possible failure for the cells to read out detectable differentiation to particular lineages, which may be due to failure in reaching suitable microenvironments in vivo, an insufficient expansion for detection in vivo, or the stochastic nature of lineage commitment, at least in vitro.
The use of pluripotential of lineage committed progenitor cells circumvents many of the problems that would arise from the transfer of mature cells. However, such progenitor cells must be separated from other hematopoietic cells. Separation requires identification of the cell and characterization of phenotypic differences that can be utilized in a separation procedure. Cells that are amenable to genetic manipulation are particularly desirable.
Relevant Literature
A number of review articles have been published addressing the phenotype of cells in hematopoietic lineages. Overall development of the hematolymphoid system is discussed in Orkin (1996)
Curr. Opin. Genet. Dev
. 6:597-602. The role of transcriptional factors in the regulation of hematopoietic differentiation is discussed in Georgopoulos et al. (1997)
Annu. Rev. Immunol
. 15:155-176; and Singh (1996)
Curr. Opin. Immunol
. 8:160-165.
References
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).
Spangrude, G. J., Heimfeld, S. & Weissman, I. L. Purification and characterization of mouse hematopoietic stem cells.
Science
241, 58-62 (1988)
Kondo, M., Weissman, I. L. & Akashi, K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow.
Cell
91, 661-672 (1997).
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).
Ogawa, M. Differentiation and proliferation of hematopoietic stem cells.
Blood
81, 2844-2853 (1993).
Heimfeld, S., Hudak, S., Weissman, I. & Rennick, D. The in vitro response of phenotypically defined mouse stem cells and myeloerythroid progenitors to single or multiple growth factors.
Proc Natl Acad Sci USA
88, 9902-9906 (1991).
Siminovitch, L., McCulloch, E. A., and Till, J. E. The distribution of colony-forming cells among spleen colonies.
J. cell comp. Physiol
. 62, 327-336 (1963).
Magli, M. C., Iscove, N. N. & Odartchenko, N. Transient nature of early hematopoietic spleen colonies.
Nature
295, 527-529 (1982).
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).
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.
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Pevny, L., et al. Erythroid differentiation in chimeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1
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349, 257-260 (1991).
Zon, L. I., Youssoufian, H., Mather, C., Lodish, H. F. & Orkin, S. H. Activation of the erythropoietin receptor promoter by transcription factor GATA-1
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88, 10638-10641 (1991).
Suda, J., Suda, T. & Ogawa, M. Analysis of differentiation of mouse hemopoietic stem cells in culture by sequential replating of paired progenitors.
Blood
64, 393-399 (1984).
Enver, T., Heyworth, C. M. & Dexter, T. M. Do stem cells play dice!
Blood
92, 348-351; discussion 352 (1998).
Metcalf, D. Lineage commitment and maturation in hematopoietic cells: the case for extrinsic regulation.
Blood
92, 345-347; discussion 352 (1998).
Traver, D., Akashi, K., Weissman, I. L. & Lagasse, E. Mice defective in two apoptosis pathways in the myeloid lineage develop acute myeloblastic leukemia.
Immunity
9, 47-57 (1998).
Morrison, S. J., Wandycz, A. M., Akashi, K., Globerson, A. & Weissman, I. L. The aging of hematopoietic stem cells.
Nat Med
2, 1011-1016 (1996).
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
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SUMMARY OF THE INVENTION
A substantially enriched mammalian hematopoietic cell subpopulation is provided, which is characterized by progenitor cell activity for myeloid lineages, but lacking the potential to differentiate into lymphoid lineages. This population is called the common myeloid progenitor cell (CMP). Methods are provided for the isolation and culture of these subpopulations. The CMP population gives rise to all myeloid lineages, and can give rise to two additional progenitor populations that are exclusively committed to either the erythroid/megakaryocytic (MEP) or myelomonocytic lineages (GMP). Both MEP and GMP can be substantially enriched, isolated and cultured. The three progenitor populations are useful in transplantation, for experimental evaluation, and as a source of lineage and cell specific products, including mRNA species useful in identifying genes specifically expressed in these cells, and as targets for the discovery of factors or molecules that can affect them.


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Enver et al. (Jul. 15, 1998), “De Stem Cells Play Dice?”Blood, vol. 92(2):348-351.
Georgopoulos et al. (1997), “The Role of the Ikaros Gene in Lymphocyte Development and Homeostasis.”Annu. Rev. Immunol., vol. 15:155-176.
Heimfeld et al. (Nov. 1991), “The in vitro Response of Phenotypically Defined Mouse Stem Cells and Myeloerythroid Progenitors to Single or Multiple Growth Factors.”Proc. Natl. Acad. Sci. USA, vol. 88:9902-9906.
Metcalf, Donald (Jul. 15, 1998), “Lineage Commitment and Maturation in Hematopoietic Cells: The Case for Extrinsic Regulation.”Blood, vol. 92(2):345-352.
Kondo et al. (Nov. 28, 1997), “Identification of Clonogenic Common Lymphoid Progenitors in Mouse Bone Marrow.”Cell, vol. 91:661-672.
Magli et al. (Feb. 11, 1982), “Transient Nature of Early Hematopoeitic Spleen Colonies.”Nature, vol. 295-527-529.
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Morrison et al. (Sep. 1996), “The Aging

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