Use of Axl, a therapeutic target in AML, to mediate stroma-induced chemoresistance.

7027 Background: Axl, the receptor for Growth Arrest-specific protein 6 (Gas6) plays a role in AML pathobiology (Blood Suppl. Nov 2011; 118: 940). Here, we investigated whether Axl represents a therapeutic target in AML. Methods: Gas6 levels were measured by ELISA and immunohistochemistry. Axl expression was detected by flow cytometry. Co-cultures of (murine) BM stroma cells (primary, OP9, S17) with Mv4-11 and OCI-AML5 cell lines were performed. Results: We found (i) higher expression of Axl in AML BM compared to healthy BM donors (66.20 ± 10.87 vs. 0.65 ± 0.10 %; n=8/6; p<0.05); (ii) Axl expression by 68 ± 31% of AML blasts and (iv) higher expression of Axl by CD34+CD38- AML stem cells compared to healthy CD34+CD38- BM stem cells (58.43 ± 4.63 % vs. 6.00 ± 2.01 %; n=7/6; p<0.05). The Axl inhibitor BGB324 dose-dependently inhibited proliferation of primary AML cells with a mean IC50 of 1.8 µM. Sensitivity to BGB324 (i.e. a lower IC50) correlated with Axl expression on leukemia cells (Pearson’s r = -0.9656...