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ACUTE MYELOID LEUKEMIA

Leukotrienes promote stem cell self-renewal and chemoresistance in acute myeloid leukemia

Leukemia volume 36, pages 1575–1584 (2022)Cite this article

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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.

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Fig. 1: ALOX5 expression is upregulated in AML cells.
Fig. 2: Loss of ALOX5 affects LSC self-renewal and maintenance.
Fig. 3: ALOX5 depletion affects signaling pathways required for LSC survival and function.
Fig. 4: ALOX5 is induced with DNR treatment and ectopic ALOX5 expression increases chemoresistance.
Fig. 5: The enzymatic activity of ALOX5 is required for the chemoresistance of AML cells.
Fig. 6: BLTR axis downstream of ALOX5 is necessary for AML cell survival.

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Acknowledgements

The authors thank Drs. Neil Rosen and Ross L. Levine for scientific discussions and Memorial Sloan Kettering Cancer Center for use of its Shared Services (Flow Cytometry Core, Integrated Genomics Operation, and Molecular Cytology Core).

Funding

This work was supported by the National Institutes of Health grant 5T32GM008539 for pre-doctoral training in Molecular Biology, the National Center for Advancing Translational Sciences (NCATS) grant TL1TR000459 of the Clinical and Translational Science Center at Weill Cornell Medical College (AWS), and the National Cancer Center (NCC) Postdoctoral Fellowship (Award ID AWD00005314) (SC). This work was also supported by the NIH/NCI (5 R01 CA164120-03), and the Leukemia and Lymphoma Society Scholar Award Program (CYP).

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Author notes

  1. Faye Feller

    Present address: Geron Corporation, Parsippany-Troy Hills, NJ, United States

  2. Mona Khalaj

    Present address: L.E.K. Consulting, San Francisco, CA, United States

  3. These authors contributed equally: Alec W. Stranahan, Iryna Berezniuk.

Authors and Affiliations

  1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States

    Alec W. Stranahan, Faye Feller & Mona Khalaj

  2. Biochemistry, Cell, and Molecular Biology Program, Weill Cornell Medicine Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, United States

    Alec W. Stranahan & Mona Khalaj

  3. Pathology, New York University School of Medicine, New York, NY, United States

    Iryna Berezniuk, Sohini Chakraborty & Christopher Y. Park

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Contributions

Contribution: AWS, FF, IB, and CYP conceived and designed the study; AWS and MK acquired the mouse data; AWS and CYP analyzed and interpreted the mouse data; IB and SC carried out BLTR related experiments and analysis; SC performed the formal analysis of the transcriptomic data; IB performed and analyzed the experiments involving primary AML specimens; AWS, IB, and CYP wrote, reviewed, and/or revised the manuscript; MK provided technical or material support; and CYP supervised the study.

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Correspondence to Christopher Y. Park.

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Stranahan, A.W., Berezniuk, I., Chakraborty, S. et al. Leukotrienes promote stem cell self-renewal and chemoresistance in acute myeloid leukemia. Leukemia 36, 1575–1584 (2022). https://doi.org/10.1038/s41375-022-01579-0

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