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

Scientific Reports
Yungui WangXi Jiang

Abstract

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 and chromatin immunoprecipitation (ChIP) assays, we found that ALOX5 is especially down-regulated in MLL-rearranged AML, via transcription repression mediated by Polycomb repressive complex 2 (PRC2). 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. Stat and K-Ras signaling pathways were negatively correlated with Alox5 overexpression in MLL-AF9-leukemic blast cells; inhibition of the above signaling pathways mimicked the drug-sensitizing effect of ALOX5 in AML cells. Collectively, our work shows that ALOX5 plays...Continue Reading

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Citations

Jul 14, 2018·BioMed Research International·Jiaqi TanJianfeng Zhou
Mar 3, 2020·Prostaglandins, Leukotrienes, and Essential Fatty Acids·Samuel J PoirierMarc E Surette
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Datasets Mentioned

BETA
GSE34184
GSE30285
43
GSE94840
GSE62190

Methods Mentioned

BETA
PCR
immunoprecipitation
Flow cytometry
transfection

Software Mentioned

GraphPad Genomics Suite
Fitch
Gene Set Enrichment Analysis ( GSEA
TIGR Mutiple Array Viewer TMeV
TMeV package TIGR
Partek Genomics Suite
Gene Set Enrichment Analysis ( GSEA )
Bioconductor R
GraphPad Prism

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