Abstract:
:The SRC family kinases (SFKs) and the receptor tyrosine kinase c-Kit are activated in human acute myeloid leukemia (AML) cells. We show here that the SFKs LYN, HCK, or FGR are overexpressed and activated in AML progenitor cells. Treatment with the SFK and c-KIT inhibitor dasatinib selectively inhibits human AML stem/progenitor cell growth in vitro. Importantly, dasatinib markedly increases the elimination of AML stem cells capable of engrafting immunodeficient mice by chemotherapeutic agents. In vivo dasatinib treatment enhances chemotherapy-induced targeting of primary murine AML stem cells capable of regenerating leukemia in secondary recipients. Our studies suggest that enhanced targeting of AML cells by the combination of dasatinib with daunorubicin may be related to inhibition of AKT-mediated human mouse double minute 2 homolog phosphorylation, resulting in enhanced p53 activity in AML cells. Combined treatment using dasatinib and chemotherapy provides a novel approach to increasing p53 activity and enhancing targeting of AML stem cells.
journal_name
Bloodjournal_title
Bloodauthors
Dos Santos C,McDonald T,Ho YW,Liu H,Lin A,Forman SJ,Kuo YH,Bhatia Rdoi
10.1182/blood-2012-11-466425subject
Has Abstractpub_date
2013-09-12 00:00:00pages
1900-13issue
11eissn
0006-4971issn
1528-0020pii
blood-2012-11-466425journal_volume
122pub_type
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