ALOX5 exhibits anti-tumor and drug-sensitizing effects in MLL-rearranged leukemia.
Sci Rep, 2017/05/12;7(1):1853.
Wang Y[1, 2, 3], Skibbe JR[2], Hu C[1, 2, 3], Dong L[2], Ferchen K[2], Su R[2], Li C[1, 2], Huang H[3, 4], Weng H[2, 3], Huang H[2], Qin X[2], Jin J[1], Chen J[5, 6], Jiang X[7, 8]
Affiliations
PMID: 28500307DOI: 10.1038/s41598-017-01913-y
Impact factor: 4.996
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 a moderate anti-tumor role and functions as a drug sensitizer, with a therapeutic potential, in MLL-rearranged AML.
MeSH terms
Animals; Arachidonate 5-Lipoxygenase; Biopsy; Bone Marrow; Bone Marrow Cells; Disease Models, Animal; Drug Resistance, Neoplasm; Gene Expression Regulation, Leukemic; Gene Rearrangement; Humans; Leukemia, Myeloid, Acute; Mice; Myeloid-Lymphoid Leukemia Protein; Signal Transduction
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