Abstract

New approaches to define the abnormal signal transduction pathways used by cellular oncogenes in the generation of cancer are needed. This grant will refine and implement a primary genetic screen to identify the cellular components critical for the creation of leukemias by the Bcr-Abl oncogene associated with Philadelphia chromosome positive human leukemias. The screening approach is based on the rescue of a series of partial loss of function mutants of Bcr-Abl, which are tyrosine kinase active but defective in fibroblast and hematopoietic transformation assays. Genes capable of rescuing a strong agar growth phenotype are selected following transfer of cDNA libraries cloned in retroviral vectors into the Bcr-Abl mutant containing cells. The basic concept of the screen has been demonstrated to work, and several novel genes are under investigation. This type of unbiased screen for genes which interact to create the transformed state in mammalian cells should provide insights about the pathogenesis of leukemia and other cancers.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076204-04
Application #
6362635
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mufson, R Allan
Project Start
1998-03-01
Project End
2003-02-28
Budget Start
2001-04-06
Budget End
2002-02-28
Support Year
4
Fiscal Year
2001
Total Cost
$407,817
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095

  Publications

Wong, S; McLaughlin, J; Cheng, D et al. (2004) Sole BCR-ABL inhibition is insufficient to eliminate all myeloproliferative disorder cell populations. Proc Natl Acad Sci U S A 101:17456-61
Kharas, Michael G; Deane, Jonathan A; Wong, Stephane et al. (2004) Phosphoinositide 3-kinase signaling is essential for ABL oncogene-mediated transformation of B-lineage cells. Blood 103:4268-75
Wong, Stephane; McLaughlin, Jami; Cheng, Donghui et al. (2003) IL-3 receptor signaling is dispensable for BCR-ABL-induced myeloproliferative disease. Proc Natl Acad Sci U S A 100:11630-5
Wong, Stephane; McLaughlin, Jami; Cheng, Donghui et al. (2003) Cell context-specific effects of the BCR-ABL oncogene monitored in hematopoietic progenitors. Blood 101:4088-97
Kabarowski, Janusz H S; Xu, Yan; Witte, Owen N (2002) Lysophosphatidylcholine as a ligand for immunoregulation. Biochem Pharmacol 64:161-7
Le, Lu Q; Kabarowski, Janusz H S; Wong, Stephane et al. (2002) Positron emission tomography imaging analysis of G2A as a negative modifier of lymphoid leukemogenesis initiated by the BCR-ABL oncogene. Cancer Cell 1:381-91
Le, L Q; Kabarowski, J H; Weng, Z et al. (2001) Mice lacking the orphan G protein-coupled receptor G2A develop a late-onset autoimmune syndrome. Immunity 14:561-71
Zhu, K; Baudhuin, L M; Hong, G et al. (2001) Sphingosylphosphorylcholine and lysophosphatidylcholine are ligands for the G protein-coupled receptor GPR4. J Biol Chem 276:41325-35
Kabarowski, J H; Zhu, K; Le, L Q et al. (2001) Lysophosphatidylcholine as a ligand for the immunoregulatory receptor G2A. Science 293:702-5
Era, T; Witte, O N (2000) Regulated expression of P210 Bcr-Abl during embryonic stem cell differentiation stimulates multipotential progenitor expansion and myeloid cell fate. Proc Natl Acad Sci U S A 97:1737-42

Showing the most recent 10 out of 14 publications