Chronic myelogenous leukemia (CML) is a malignancy of a pluripotent hematopoietic stem cell. The disease is characterized by the presence of a specific chromosomal translocation, t(9;22), which results in the production of a 210 kDa fusion protein termed Bcr-Abl. As compared to c-Abl, the fusion protein, Bcr-Abl, has elevated tyrosine kinase activity. Over the past 5 years, numerous substrates of the Bcr-Abl tyrosine kinase have been identified and a variety of signaling pathways have been shown to be activated in Bcr-Abl-expressing cells. However, the necessity of most of these pathways and tyrosine phosphorylated protein for Bcr-Abl function remain unclear. Given the complexity of Bcr-Abl, it is the applicant's belief that a combination of approaches is required to dissect Bcr-Abl function. This includes a mutagenic structure-function analysis, a biochemical analysis of protein-protein interactions, and a genetic approach. This proposal will continue the studies by Bcr-Abl function by: 1. Analyzing Bcr-Abl mutants for defects in transforming abilities in vitro and in vivo; 2. Performing biochemical analyses of Bcr-Abl kinase regulation by tyrosine phosphorylation and determining affinities of interactions with various signaling proteins, and 3. Determining the necessity of various signaling proteins for Bcr-Abl function by analyzing cell lines or mice deficient in specific proteins. Through these studies the applicant hopes to gain greater insight into the molecular mechanism of action of this activated tyrosine kinase and that this information may be applied to disorders in which activated tyrosine kinase signaling pathways have a role.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA065823-08
Application #
6512849
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mufson, R Allan
Project Start
1995-07-01
Project End
2005-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
8
Fiscal Year
2002
Total Cost
$305,775
Indirect Cost
Name
Oregon Health and Science University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
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Pietarinen, Paavo O; Eide, Christopher A; Ayuda-DurĂ¡n, Pilar et al. (2017) Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors. Oncotarget 8:22606-22615
Watanabe-Smith, Kevin; Godil, Jamila; Agarwal, Anupriya et al. (2017) Analysis of acquired mutations in transgenes arising in Ba/F3 transformation assays: findings and recommendations. Oncotarget 8:12596-12606
Ma, Leyuan; Boucher, Jeffrey I; Paulsen, Janet et al. (2017) CRISPR-Cas9-mediated saturated mutagenesis screen predicts clinical drug resistance with improved accuracy. Proc Natl Acad Sci U S A 114:11751-11756
Zabriskie, M S; Eide, C A; Yan, D et al. (2016) Extreme mutational selectivity of axitinib limits its potential use as a targeted therapeutic for BCR-ABL1-positive leukemia. Leukemia 30:1418-21
O'Hare, Thomas; Zabriskie, Matthew S; Eide, Christopher A et al. (2011) The BCR-ABL35INS insertion/truncation mutant is kinase-inactive and does not contribute to tyrosine kinase inhibitor resistance in chronic myeloid leukemia. Blood 118:5250-4
Eide, Christopher A; Adrian, Lauren T; Tyner, Jeffrey W et al. (2011) The ABL switch control inhibitor DCC-2036 is active against the chronic myeloid leukemia mutant BCR-ABLT315I and exhibits a narrow resistance profile. Cancer Res 71:3189-95
Johnson, Kara J; Griswold, Ian J; O'Hare, Thomas et al. (2009) A BCR-ABL mutant lacking direct binding sites for the GRB2, CBL and CRKL adapter proteins fails to induce leukemia in mice. PLoS One 4:e7439
Snead, Jennifer L; O'Hare, Thomas; Adrian, Lauren T et al. (2009) Acute dasatinib exposure commits Bcr-Abl-dependent cells to apoptosis. Blood 114:3459-63

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