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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA086017-05
Application #
6756399
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mufson, R Allan
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
5
Fiscal Year
2004
Total Cost
$338,685
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Barkal, Amira A; Weiskopf, Kipp; Kao, Kevin S et al. (2018) Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nat Immunol 19:76-84
Betancur, Paola A; Abraham, Brian J; Yiu, Ying Y et al. (2017) A CD47-associated super-enhancer links pro-inflammatory signalling to CD47 upregulation in breast cancer. Nat Commun 8:14802
Wernig, Gerlinde; Chen, Shih-Yu; Cui, Lu et al. (2017) Unifying mechanism for different fibrotic diseases. Proc Natl Acad Sci U S A 114:4757-4762
Gordon, Sydney R; Maute, Roy L; Dulken, Ben W et al. (2017) PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 545:495-499
McCracken, Melissa N; George, Benson M; Kao, Kevin S et al. (2016) Normal and Neoplastic Stem Cells. Cold Spring Harb Symp Quant Biol 81:1-9
Cheah, Ming T; Chen, James Y; Sahoo, Debashis et al. (2015) CD14-expressing cancer cells establish the inflammatory and proliferative tumor microenvironment in bladder cancer. Proc Natl Acad Sci U S A 112:4725-30
Weissman, Irving L (2015) Stem cells are units of natural selection for tissue formation, for germline development, and in cancer development. Proc Natl Acad Sci U S A 112:8922-8
Feng, Mingye; Chen, James Y; Weissman-Tsukamoto, Rachel et al. (2015) Macrophages eat cancer cells using their own calreticulin as a guide: roles of TLR and Btk. Proc Natl Acad Sci U S A 112:2145-50
Weissman, Irving (2015) Evolution of normal and neoplastic tissue stem cells: progress after Robert Hooke. Philos Trans R Soc Lond B Biol Sci 370:20140364
McCracken, Melissa N; Cha, Adriel C; Weissman, Irving L (2015) Molecular Pathways: Activating T Cells after Cancer Cell Phagocytosis from Blockade of CD47 ""Don't Eat Me"" Signals. Clin Cancer Res 21:3597-601

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