Leukotrienes promote stem cell self-renewal and chemoresistance in acute myeloid leukemia Journal Article
| Authors: | Stranahan, A. W.; Berezniuk, I.; Chakraborty, S.; Feller, F.; Khalaj, M.; Park, C. Y. |
| Article Title: | Leukotrienes promote stem cell self-renewal and chemoresistance in acute myeloid leukemia |
| Abstract: | Acute myeloid leukemia (AML) is characterized by poor clinical outcomes due to high rates of relapse following standard-of-care induction chemotherapy. While many pathogenic drivers have been described in AML, our understanding of the molecular mechanisms mediating chemotherapy resistance remains poor. Therefore, we sought to identify resistance genes to induction therapy in AML and elucidated ALOX5 as a novel mediator of resistance to anthracycline-based therapy. ALOX5 is transcriptionally upregulated 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. In vitro, and in vivo genetic, and pharmacologic perturbation studies confirm that ALOX5 positively regulates the leukemogenic potential of AML LSCs, and its 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 via modulating the synthesis of LTB4 and its binding to LTB receptor (BLTR). Our study reveals a previously unrecognized role of LTs in AML pathogenesis and chemoresistance, whereby inhibition of ALOX5 mediated LTB4 synthesis and function could be combined with standard chemotherapy, to enhance the overall therapeutic efficacy in AML. © 2022, The Author(s), under exclusive licence to Springer Nature Limited. |
| Keywords: | controlled study; protein expression; treatment response; human cell; genetics; leukemia, myeloid, acute; drug efficacy; antineoplastic agents; cancer patient; antineoplastic agent; genetic analysis; protein function; metabolism; cell survival; in vivo study; in vitro study; drug resistance; pathology; drug resistance, neoplasm; stem cell; biosynthesis; regulatory mechanism; messenger rna; neoplastic stem cells; gene identification; leukemogenesis; cancer stem cell; daunorubicin; upregulation; arachidonate 5 lipoxygenase; hematopoietic stem cell; anthracycline; lipogenesis; receptor binding; blast cell; acute myeloid leukemia; cell self-renewal; cell self renewal; leukotriene b4 receptor; humans; human; article; acute myeloid leukemia cell line; leukotriene b4; leukotriene; alox5 gene |
| Journal Title: | Leukemia |
| Volume: | 36 |
| Issue: | 6 |
| ISSN: | 0887-6924 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2022-06-01 |
| Start Page: | 1575 |
| End Page: | 1584 |
| Language: | English |
| DOI: | 10.1038/s41375-022-01579-0 |
| PUBMED: | 35461365 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 July 2022 -- Source: Scopus |
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