Leukemogenic nucleophosmin mutation disrupts the transcription factor hub regulating granulo-monocytic fates

Xiaorong Gu, Quteba Ebrahem, Reda Z Mahfouz, Metis Hasipek, Francis Enane, Tomas Radivoyevitch, Nicolas Rapin, Bartlomiej Przychodzen, Zhenbo Hu, Ramesh Balusu, Claudiu V Cotta, David Wald, Christian Argueta, Yosef Landesman, Maria Paola Martelli, Brunangelo Falini, Hetty Carraway, Bo T Porse, Jaroslaw P Maciejewski, Babal K JhaYogen Saunthararajah

    94 Citationer (Scopus)

    Abstract

    Nucleophosmin (NPM1) is amongst the most frequently mutated genes in acute myeloid leukemia (AML). It is not known, however, how the resulting oncoprotein mutant-NPM1 is leukemogenic. To reveal the cellular machinery in which NPM1 participates in myeloid cells, we analyzed the endogenous NPM1 protein-interactome by mass-spectrometry, and discovered abundant amounts of the master transcription factor driver of monocyte lineage-differentiation PU.1 (SPI1). Mutant-NPM1, which aberrantly accumulates in cytoplasm, dislocated PU.1 into cytoplasm with it. CEBPA and RUNX1, the master transcription factors that collaborate with PU.1 to activate granulo-monocytic lineage-fates, remained nuclear, but without PU.1, their coregulator interactions were toggled from coactivators to corepressors, repressing instead of activating greater than 500 granulocyte and monocyte terminal-differentiation genes. An inhibitor of nuclear export, selinexor, by locking mutant-NPM1/PU.1 in the nucleus, activated terminal monocytic fates. Direct depletion of the corepressor DNA methyltransferase 1 (DNMT1) from the CEBPA/RUNX1 protein interactome using the clinical drug decitabine activated terminal granulocytic fates. Together, these non-cytotoxic treatments extended survival by greater than 160 days versus vehicle in a patient-derived xenotransplant model of NPM1/FLT3-mutated AML. In sum, mutant-NPM1 represses monocyte and granulocyte terminal-differentiation by disrupting PU.1/CEBPA/RUNX1 collaboration, a transforming action that can be reversed by pharmacodynamically-directed dosing of clinical small molecules.

    OriginalsprogEngelsk
    TidsskriftThe Journal of clinical investigation
    Vol/bind128
    Udgave nummer10
    Sider (fra-til)4260-4279
    ISSN0021-9738
    DOI
    StatusUdgivet - 1 okt. 2018

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