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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Inflammation Pharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1520507
This article is part of the Research Topic Inflammation and Lipid Signaling in Disease Pathogenesis View all 9 articles

MLL-AF4 upregulates 5-lipoxygenase expression in t(4;11) leukemia cells via the ALOX5 core promoter

Provisionally accepted
Marius Hyprath Marius Hyprath Maximilian Molitor Maximilian Molitor Ilona Schweighöfer Ilona Schweighöfer Rolf Marschalek Rolf Marschalek Dieter Steinhilber Dieter Steinhilber *
  • Goethe University Frankfurt, Frankfurt, Germany

The final, formatted version of the article will be published soon.

    5-Lipoxygenase (5-LO), encoded by the gene ALOX5, is implicated in several pathologies. As key enzyme in leukotriene biosynthesis, 5-LO plays a central role in inflammatory diseases, but the 5-LO pathway has also been linked to development of certain hematological and solid tumor malignancies. Of note, previous studies have shown that the leukemogenic fusion protein MLL-AF4 strongly increases ALOX5 gene promoter activity. Here, we investigate the upregulation of ALOX5 gene expression by MLL-AF4. Using reporter assays, we first identified the tandem GC box within the ALOX5 promotor sequence as the main target of MLL-AF4.Subsequently, we narrowed down the domains within the MLL-AF4 protein responsible for ALOX5 promoter activation. Our findings indicate that MLL-AF4 binds to the ALOX5 promoter via its CXXC domain and that the AF9ID, pSER and CHD domains redundantly activate transcriptional elongation. Knockdown of the MLL-AF4 gene in the human B cell line SEM revealed that MLL-AF4 is an inducer of ALOX5 gene expression and activity in leukemic cells with lymphoid properties. Finally, we found that the MLL-AF4-related protein MLL-AF9, a driver of acute myeloid leukemia, similarly acts on the ALOX5 promoter. Taken together, we show that two prominent MLL fusion proteins are ALOX5 gene inducers in cells with lymphoid features.

    Keywords: 5-lipoxygenase, MLL, MLL-AF4, Leukemia, leukocyte, leukotriene

    Received: 31 Oct 2024; Accepted: 24 Dec 2024.

    Copyright: © 2024 Hyprath, Molitor, Schweighöfer, Marschalek and Steinhilber. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Dieter Steinhilber, Goethe University Frankfurt, Frankfurt, Germany

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