GSE200614
Alox5 mediates survival of LSCs, and chemoresistance in AML via LTB4-BLTR signaling
Acute myeloid leukemia (AML) is characterized by poor clinical outcomes due to high rates of relapse following induction chemotherapy. While many pathogenic drivers have been described in AML, our understanding of the molecular mechanisms mediating chemotherapy resistance remains poor, and initial management of AML continues to rely on standard induction chemotherapy for many patients. Given the importance of identifying new approaches to improve the efficiency of induction therapy in AML, we sought to identify resistance genes to induction therapy in AML and identified ALOX5 is a novel mediator of resistance to anthracycline based therapy.  ALOX5 mRNA is expressed at high levels in AML patient blasts in comparison to normal hematopoietic stem/progenitor cells (HSPCs) and ALOX5 mRNA and protein expression is increased in response to induction therapy. Genetic and pharmacologic perturbations of ALOX5 function in vitro and in vivo confirm that ALOX5 positively regulates the leukemogenic potential of AML LSCs, while ALOX5 loss does not significantly affect the function of normal HSPCs. ALOX5 mediates resistance to daunorubicin (DNR) and promotes AML cell survival and maintenance through its leukotriene (LT) synthetic capacity. Specifically, the ALOX5 dependent resistance phenotype depends on its ability to synthesize LTB4 and bind to the LTB receptor (BLTR). Overall, our studies reveal a previously unrecognized role of LT's in AML pathogenesis and chemoresistance, and provide a potential novel strategy to enhance the therapeutic efficacy of induction chemotherapy in AML. Overall design: Leukemic mice were generated by retroviral transduction of mouse HPSCs with the MLL-AF9 oncogene fusion following established protocol. Double FACS-sorted Lin-Sca-1+c-Kit+ cells (LSK) were isolated from the bone marrow of either C57BL/6J WT or Alox5-/- . Following retroviral transduction with MLL-AF9, GFP+ cells were transplanted into irradiated primary C57BL/6J recipients.