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KMT2A oncoproteins induce epigenetic resistance to targeted therapies

Derek H Janssens, Melodie Duran, Dominik J Otto

    Biorxiv : the Preprint Server for Biology
    |January 18, 2024
    PubMed

    Insights

    KMT2A oncoproteins drive leukemia by disrupting gene expression, with levels dictating ALL or AML programs. Therapy can induce lineage switching, leading to resistance via epigenetic changes marked by ENL.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Epigenetics

    Background:

    • Chromosomal translocations involving KMT2A generate oncogenic fusion proteins.
    • These oncoproteins disrupt normal gene expression regulation, particularly during development.
    • KMT2A rearrangements are implicated in various leukemias.

    Purpose of the Study:

    • To profile oncoprotein-target sites in KMT2A-rearranged leukemia samples.
    • To understand the variability and dynamic regulation of oncoprotein genomic enrichment.
    • To investigate the mechanisms behind therapy-induced lineage switching and treatment resistance.

    Main Methods:

    • Genomic profiling of oncoprotein-target sites in 36 KMT2A-rearranged leukemia samples.
    • Analysis of samples with lymphoid-to-myeloid lineage switching.
    • Investigation of oncoprotein levels and binding patterns in relation to gene expression programs (ALL, AML, GMP).
    • Assessment of ENL cofactor persistence in a therapy-resistant sample.

    Main Results:

    • Oncoprotein genomic enrichment is highly variable and dynamically regulated.
    • High oncoprotein levels activate either ALL (pro-B-cell genes) or AML (hematopoietic stem cell genes) programs.
    • Lineage-switching samples show reduced oncoprotein levels and activation of GMP genes.
    • In one case, ENL persisted on target loci despite undetectable oncoprotein and menin levels during revumenib treatment.

    Conclusions:

    • KMT2A oncoproteins can promote lineage switching through dynamic chromatin binding.
    • Epigenetic lesions marked by ENL may contribute to resistance against targeted therapies.
    • Understanding these mechanisms is crucial for developing effective leukemia treatments.

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