BCR/ABL oncogenic tyrosine kinase is present in most chronic myelogenous leukemias (CML) and a cohort of acute lymphocytic leukemias (ALL). Our previous studies indicated that BCR/ABL activates multiple signaling pathways responsible for the neoplastic phenotype of leukemic cells. SH2 and SH3 domains of BCR/ABL play an essential role in BCR/ABL-induced leukemogenesis. SH2 domain activates PI-3k/Akt pathway, and SH3 domain regulates integrins and affects adhesion, invasion and homing properties of leukemia cells. Both SH3 and SH2 domains of BCR/ABL regulate STAT5 activation, which seems to play an important role in protection from apoptosis, cell cycle progression, resistance to DNA damaging agents (cytostatic drugs) and leukemogenic transformation. Several downstream effectors of the BCR/ABL SH3+SH2 domains->STAT5 signaling pathway have been identified, which may contribute to these phenomena. The objective of this proposal is to further investigate the molecular mechanisms of BCR/ABL-mediated leukemogenesis in particular to identify and describe the functions of genes regulated by signaling from BCR/ABL SH3+SH2 domains->STAT5. In addition, the contribution of these signaling pathways to the blastic transformation of chronic myelogenous leukemia cells will also be examined.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Hematology Subcommittee 2 (HEM)
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Mufson, R Allan
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Temple University
Other Health Professions
Schools of Arts and Sciences
United States
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Falinski, Rafal; Nieborowska-Skorska, Margaret; Skorski, Tomasz (2012) BCR-ABL1 kinase facilitates localization of acetylated histones 3 and 4 on DNA double-strand breaks. Leuk Res 36:241-4
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Slupianek, Artur; Poplawski, Tomasz; Jozwiakowski, Stanislaw K et al. (2011) BCR/ABL stimulates WRN to promote survival and genomic instability. Cancer Res 71:842-51
Slupianek, A; Jozwiakowski, S K; Gurdek, E et al. (2009) BCR/ABL kinase interacts with and phosphorylates the RAD51 paralog, RAD51B. Leukemia 23:2308-10
Cramer, Kimberly; Nieborowska-Skorska, Margaret; Koptyra, Mateusz et al. (2008) BCR/ABL and other kinases from chronic myeloproliferative disorders stimulate single-strand annealing, an unfaithful DNA double-strand break repair. Cancer Res 68:6884-8
Stoklosa, Tomasz; Poplawski, Tomasz; Koptyra, Mateusz et al. (2008) BCR/ABL inhibits mismatch repair to protect from apoptosis and induce point mutations. Cancer Res 68:2576-80
Rink, Lori; Slupianek, Artur; Stoklosa, Tomasz et al. (2007) Enhanced phosphorylation of Nbs1, a member of DNA repair/checkpoint complex Mre11-RAD50-Nbs1, can be targeted to increase the efficacy of imatinib mesylate against BCR/ABL-positive leukemia cells. Blood 110:651-60
Nieborowska-Skorska, Margaret; Stoklosa, Tomasz; Datta, Mandrita et al. (2006) ATR-Chk1 axis protects BCR/ABL leukemia cells from the lethal effect of DNA double-strand breaks. Cell Cycle 5:994-1000
Nieborowska-Skorska, Margaret; Hoser, Grazyna; Rink, Lori et al. (2006) Id1 transcription inhibitor-matrix metalloproteinase 9 axis enhances invasiveness of the breakpoint cluster region/abelson tyrosine kinase-transformed leukemia cells. Cancer Res 66:4108-16
Koptyra, Mateusz; Falinski, Rafal; Nowicki, Michal O et al. (2006) BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood 108:319-27

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