The myeloid leukemias are a major cause of human mortality and morbidity. Since molecular defects in cancer cells often involve genes that regulate programmed cell death (PCD), Dr. Weissman has created transgenic mice that constitutively express the human anti-apoptosis gene bcl-2 in monocytes, neutrophils, and their common progenitors by using the hMRP8 promoter. hMRP8bcl-2 mice develop a massive buildup of stem cells, myelomonocytic progenitors, and monocytes in a syndrome that mimics human chronic myelomonocytic leukemia (CMML). Despite the development of CMML, hMRP8bcl-2 mice rarely progress to acute myeloid leukemia (AML). Primitive myeloid blast cells from hMRP8bcl-2 mice express the Fas receptor and, despite overexpression of Bcl-2, are induced to die by Fas ligation. To provide a further block in PCD in the myeloid lineage, he crossed hMRP8bcl-2 mice with Fas-deficient Fas lpr/lpr mice. Fifteen percent of Fas lpr/lpr hMRP8bcl-2 mice developed fatal AML-M2 by 8 weeks of age, but rarely thereafter. This grant will test whether immune surveillance limits AML development past 8 weeks, and whether additional mutations in known or novel proto-oncogenes collaborate with """"""""deathless"""""""" myeloid precursors to cause AML. Transduction of myeloid progenitors from healthy Fas lpr/lpr hMRP8bcl-2 mice with (proto-) oncogenes found in human AML will be tested as candidates for leukemogenic collaboration. cDNAs differentially expressed between leukemic and non-leukemic blast cells will be identified through microarray analyses, and candidate genes will be tested as oncogene candidates. Eventually, human AMLs will be screened for homologous gene defects.
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