Abstract 2348: Low PU.1 expression not only attenuates neutrophil differentiation of AML cells but also increases resistance to cytotoxic therapies

Abstract

Inactivation of PU.1 results in a myeloid differentiation block and contributes to the pathogenesis of acute myeloid leukemia (AML). A long list of PU.1 transcriptional targets with a direct function in myeloid development exits and clearly supports its role in cellular hematopoietic differentiation processes. Furthermore, we and others showed that PU.1 positively affects cell survival, for example by directly activating the anti-apoptotic genes BCL2A1 and BCL-XL. Recently, we demonstrated that the novel PU.1 target Hexokinase 3 supports acute promyelocytic leukemia (APL) cell survival. Surprisingly, our current data indicate that knocking down PU.1 in NB4 APL significantly increased resistance in apoptosis responses to anthracyclins. These findings were confirmed in MOLM-3 AML cells. Both cell lines showed an induction of the anti-apoptotic gene CFLAR (c-FLIP). c-FLIP blocks the activation of procaspase-8 at the death-inducing signalling complex (DISC) and is involved in AML chemotherapy resistance. Using PU.1 and c-FLIP double knockdown APL cells, we could significantly restore the sensitivity to anthracyclin treatment. This indicates that the PU.1 knockdown-dependent increase of c-FLIP is responsible for the resistance towards anthracyclin treatment. Moreover, we identified the pro-apoptotic kinase DAPK2 as novel transcriptional target of PU.1 in APL cells. Interestingly, we found that inhibiting DAPK2 in APL cells significantly attenuater arsenic trioxide (ATO)-induced cell death. Together, we link PU.1 to apoptosis and resistance against antracyclins and ATO via regulating c-FLIP and DAPK2. Our data indicate that low PU.1 level found in AML patients not only contribute to a block in differentiation but also increase resistance to cytotoxic therapies in AML. Citation Format: Mario P. Tschan, Aladin Haimovici, Daniel Brigger, Anna M. Schläfli, Deborah Shan, Martin F. Fey. Low PU.1 expression not only attenuates neutrophil differentiation of AML cells but also increases resistance to cytotoxic therapies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2348. doi:10.1158/1538-7445.AM2014-2348