Chronic myelogenous leukemia (CML) is a malignancy of a pluripotent hematopoietic stem cell. The disease is characterized by the presence of a (9;22) chromosomal translocation that results in the production of a 210 kDa fusion protein termed Bcr-Abl. Compared to c-Abl, the Bcr-Abl fusion protein has elevated tyrosine kinase activity. The clinical success of a specific Abl kinase inhibitor, imatinib, has demonstrated the critical dependence of Bcr-Abl function on the kinase activity of the protein. However, imatinib is not capable of eradicating the disease and resistance to single agent imatinib, particularly in patients with advanced phase disease has been common. Thus, greater insight into the molecular mechanism of action of this activated tyrosine kinase may provide additional targets for therapy and an improved therapeutic outcome for patient with CML. Therefore, the goal of this proposal is to learn more about how Bcr-Abl functions to transform cells by determining which signaling proteins and pathways are essential for its function. The first specific aim will analyze Bcr- Abl mutants for defects in transforming abilities in vitro and in vivo. In the second aim, we will follow up on the finding that the main mechanism of acquired resistance to imatinib is mutations in the kinase domain of Abl that impair imatinib binding. These mutants present an ideal opportunity to study the regulation of the Abl kinase. In addition, the mutants allow us an opportunity to address whether these mutations affect the substrate specificity of Abl, the signaling proteins and pathways that are activated, and the transforming properties of these Bcr-Abl mutants. In that last aim, we will follow up on our finding that Bcr-Abl is unable to transform CrkL null cells and that CrkL null cells expressing Bcr-Abl have a variety of signaling defects. These defects will be analyzed to determine the mechanism by which Bcr-Abl is unable to transform CrkL null cells. Combined, these data should offer significant insights into the biology of and the mechanism of transformation by Bcr-Abl.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA065823-15
Application #
7616840
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mufson, R Allan
Project Start
2005-07-01
Project End
2011-03-17
Budget Start
2009-05-01
Budget End
2011-03-17
Support Year
15
Fiscal Year
2009
Total Cost
$310,291
Indirect Cost
Name
Oregon Health and Science University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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
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
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
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
Press, Richard D; Love, Zac; Tronnes, Ashlie A et al. (2006) BCR-ABL mRNA levels at and after the time of a complete cytogenetic response (CCR) predict the duration of CCR in imatinib mesylate-treated patients with CML. Blood 107:4250-6
Gaston, Isabelle; Johnson, Kara J; Oda, Tsukasa et al. (2004) Coexistence of phosphotyrosine-dependent and -independent interactions between Cbl and Bcr-Abl. Exp Hematol 32:113-21

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