Leukemogenic nucleophosmin mutation disrupts the transcription factor hub that regulates granulomonocytic fates

The Journal of Clinical Investigation
Xiaorong GuY Saunthararajah

Abstract

Nucleophosmin (NPM1) is among 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 (also known as 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 granulomonocytic lineage fates, remained nuclear; but without PU.1, their coregulator interactions were toggled from coactivators to corepressors, repressing instead of activating more 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 noncytotoxic treatm...Continue Reading

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Datasets Mentioned

BETA
GSM538017
GSM537983
GSM1692857

Methods Mentioned

BETA
pull-down
coimmunoprecipitation
ChIP
flow cytometry
affinity
ChIP-Seq

Software Mentioned

EaSeq
Encode
Leica Application Suite X
Morpheus
SAS
Comparative Marker Selection (
Graph Prism GraphPad
Cytoscape
BloodPool
Nuance

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