ALOX5 exhibits anti-tumor and drug-sensitizing effects in MLL-rearranged leukemia

MLL-rearranged acute myeloid leukemia (AML) remains a fatal disease with a high rate of relapse and therapeutic failure due to chemotherapy resistance. In analysis of our Affymetrix microarray profiling of human AML and normal control samples, we found that ALOX5 is especially down-regulated in MLL-rearranged AML. Our colony forming/replating and bone marrow transplantation (BMT) assays showed that Alox5 exhibited a moderate anti-tumor effect both in vitro and in vivo. Strikingly, leukemic cells with Alox5 overexpression showed a significantly higher sensitivity to the standard chemotherapeutic agents, i.e., doxorubicin (DOX) and cytarabine (Ara-C). The drug-sensitizing role of Alox5 was further confirmed in human and murine MLL-rearranged AML cell models in vitro, as well as in the in vivo MLL-rearranged AML BMT model coupled with treatment of “5+3” (i.e. DOX plus Ara-C) regimen. Our RNA-seq analysis showed that Stat and K-Ras signaling pathways were negatively correlated with Alox5 overexpression in MLL-AF9-leukemic blast cells, implying targeting those pathways likely contributes to Alox5's functions. Collectively, our work shows that ALOX5 plays a moderate anti-tumor role and functions as a drug sensitizer, with a therapeutic potential, in MLL-rearranged AML. Overall design: To delineate the potential molecular mechanism underlying the anti-tumor and drug-sensitizing effects of Alox5, we performed RNA sequencing (RNA-seq) of two pairs (4 samples) of mouse BM leukemic blast cells collected from the MA9_Ctrl and MA9_Alox5 mice in secondary BMT assays.

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Wang Y, Skibbe JR, Hu C, Dong L, Ferchen K, Su R, Li C, Huang H, Weng H, Huang H, Qin X, Jin J, Chen J, Jiang X