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

Lina Han (1, 2) , Jan Jacob Schuringa (1) , André Mulder (3) , Edo Vellenga (1)

1 Department of Hematology
2 Department of Hematology
3 Department of Clinical Chemistry

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.

Mots clés: Acute myeloid leukemia; Dasatinib; SRC family kinases; KIT mutation

Lina Han, Jan Jacob Schuringa, André Mulder, Edo Vellenga. Dasatinib impairs long-term expansion of leukemic progenitors in a subset of acute myeloid leukemia cases. Annals of Hematology, 2010, 89 (9), pp.861-871. ⟨10.1007/s00277-010-0948-7⟩. ⟨hal-00535131⟩