Mice defective in two apoptosis pathways in the myeloid lineage develop acute myeloblastic leukemia.
Fas-deficient (Fas(lpr/lpr)) mice constitutively expressing Bcl-2 in myeloid cells by the hMRP8 promoter often develop a fatal disease analogous to human acute myeloblastic leukemia (AML-M2). Hematopoietic cells from leukemic Fas(lpr/lpr)hMRP8bcl-2 animals form clonogenic blast colonies in vitro and can transfer disease to wild-type mice. In vitro ligation of Fas on Fas+/+ hMRP8bcl-2 marrow cells depletes approximately 50% of myeloid progenitor activity, demonstrating that Bcl-2 can only partially block Fas-mediated death signals in myelomonocytic progenitors. In addition, Fas(lpr/lpr) marrow contains greatly increased numbers of myeloid colony-forming cells as compared to Fas+/+ controls. Taken together, these data suggest that Fas has a novel role in the regulation of myelopoiesis and that Fas may act as a tumor suppressor to control leukemogenic transformation in myeloid progenitor cells.
Traver
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D
Department of Pathology, Stanford University School of Medicine, California 94305, USA. dtraver@leland.stanford.edu
Akashi
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K
Weissman
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IL
Lagasse
E
E
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics; D017209:Apoptosis; D001854:Bone Marrow Cells; D002135:Calcium-Binding Proteins / Q000235:genetics; D040501:Calgranulin A; D015984:Causality; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D006412:Hematopoietic Stem Cells; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000235:genetics; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation; D019014:fas Receptor / Q000235:genetics / Q000502:physiology*
D000943:Antigens, Differentiation; D002135:Calcium-Binding Proteins; D040501:Calgranulin A; D007377:Interleukin-3; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor