Fas-deficient (FaslPr/lpr/) mice constitutively expressing Bcl-2 in myeloid cells by the hMRPS promoter develop a fatal disease analogous to human acute myeloblastic leukemia (AML-M2). Hematopoietic cells from leukemic FaslPr/lpr hMRP8bcl-2 animals form clonogenic blast colonies in vitro and can transfer disease to wild-type recipient animals. These data demonstrate that loss of function Fas mutations synergistically collaborate with gain of function Bcl-2 mutations in the development of AML. In vitro ligation of Fas on Fas+/+ hMRP8bcl-2 bone 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, FaslPr/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.
|出版ステータス||出版済み - 12 1 1998|
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