Dasatinib impairs long-term expansion of leukemic progenitors in a subset of acute myeloid leukemia cases

作者：Han Lina; Schuringa Jan Jacob; Mulder Andre; Vellenga Edo^*

来源：Annals of Hematology, 2010, 89(9): 861-871.

DOI：10.1007/s00277-010-0948-7

• Acute myeloid leukemia
• Dasatinib
• SRC family kinases
• KIT mutation

A number of signaling pathways might be frequently disrupted in acute myeloid leukemia (AML). We questioned whether the dual SRC/ABL kinase inhibitor dasatinib can affect AML cells and whether differences can be observed with normal CD34(+) cells. First, we demonstrated that normal cord blood (CB) CD34(+) cells were unaffected by dasatinib at a low concentration (0.5 nM) in the long-term culture on MS5 stromal cells. No changes were observed in proliferation, differentiation, and colony formation. In a subset of AML cases (3/15), a distinct reduction in cell proliferation was observed, ranging from 48% to 91% inhibition at 0.5 nM of dasatinib, in particular, those characterized by BCR-ABL or KIT mutations. Moreover, the inhibitory effects of dasatinib were cytokine specific. Stem cell factor-mediated proliferation was significantly impaired, associated with a reduced phosphorylation of ERK1/2 and STAT5, whereas no effect was observed on interleukin-3 and thrombopoietin-mediated signaling despite SRC activation. In conclusion, this study demonstrates that dasatinib is a potential inhibitor in a subgroup of AML, especially those that express BCR-ABL or KIT mutations.

• 出版日期2010-9
• 单位中国医科大学; 哈尔滨医科大学