Mice Defective in Two Apoptosis Pathways in the Myeloid Lineage Develop Acute Myeloblastic Leukemia

Department of Developmental Biology , Stanford University, Stanford, California, United States
Immunity (Impact Factor: 21.56). 08/1998; 9(1):47-57. DOI: 10.1016/S1074-7613(00)80587-7
Source: PubMed


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.

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    • "Among the important molecules that affect the intrinsic apoptotic pathway through mitochondria, the Bcl-2 family proteins play a major role in cell survival and drug sensitivity since dysregulation of Bcl-2 family is often observed in various types of human cancer, including renal, ovarian, stomach, and brain tumors and leukemia [106–108]. It has been shown that increased expression of prosurvival Bcl-2 homologues [109] or lack of BH3-only protein expression and/or function (e.g., caused by loss of p53) [110] contributed to tumorigenesis and anticancer drug resistance. "
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    • "Another putative apoptotic mechanism in both the erythroid[86]and myeloid[87]lineages is feedback inhibition of Fas-expressing progenitor cells by Fasligand-expressing mature cells. The Fas receptor is overexpressed on CML CD34+ cells[88]and expression is enhanced by IFN-α[59]. Intuitively, this should lead to more, rather than less, CML progenitor cell loss in vivo. "
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    • "Thus, our observations strongly support the etiological relevance of cebpa mutations in patients who have AML, and inhibition of C/EBPα function by translocation products found in myeloid leukemias. Previously, induction of AML-like disease in vivo by expression of PML-RARα or BCR-ABL transgenes (34–36), by ectopic Bcl-2 expression combined with the absence of Fas signaling (37), and by ectopic AML-ETO expression in conjunction with N-ethyl-N′-nitrosourea mutagenesis (38, 39) has been observed. However, the precise mechanisms of action of translocation-derived oncoproteins remain unclear, not least because each transgenically expressed oncoprotein generally affects several cellular targets, in the case of AML-ETO and BCR-ABL including C/EBPα. "
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