TY - JOUR
T1 - Leukemogenic nucleophosmin mutation disrupts the transcription factor hub regulating granulo-monocytic fates
AU - Gu, Xiaorong
AU - Ebrahem, Quteba
AU - Mahfouz, Reda Z
AU - Hasipek, Metis
AU - Enane, Francis
AU - Radivoyevitch, Tomas
AU - Rapin, Nicolas
AU - Przychodzen, Bartlomiej
AU - Hu, Zhenbo
AU - Balusu, Ramesh
AU - Cotta, Claudiu V
AU - Wald, David
AU - Argueta, Christian
AU - Landesman, Yosef
AU - Martelli, Maria Paola
AU - Falini, Brunangelo
AU - Carraway, Hetty
AU - Porse, Bo T
AU - Maciejewski, Jaroslaw P
AU - Jha, Babal K
AU - Saunthararajah, Yogen
PY - 2018/10/1
Y1 - 2018/10/1
N2 - 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.
AB - 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.
U2 - 10.1172/JCI97117
DO - 10.1172/JCI97117
M3 - Journal article
C2 - 30015632
SN - 0021-9738
VL - 128
SP - 4260
EP - 4279
JO - The Journal of clinical investigation
JF - The Journal of clinical investigation
IS - 10
ER -