Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

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

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Gu, X, Ebrahem, Q, Mahfouz, RZ, Hasipek, M, Enane, F, Radivoyevitch, T, Rapin, N, Przychodzen, B, Hu, Z, Balusu, R, Cotta, CV, Wald, D, Argueta, C, Landesman, Y, Martelli, MP, Falini, B, Carraway, H, Porse, BT, Maciejewski, JP, Jha, BK & Saunthararajah, Y 2018, 'Leukemogenic nucleophosmin mutation disrupts the transcription factor hub regulating granulo-monocytic fates' The Journal of clinical investigation, vol. 128, no. 10, pp. 4260-4279. https://doi.org/10.1172/JCI97117

APA

Gu, X., Ebrahem, Q., Mahfouz, R. Z., Hasipek, M., Enane, F., Radivoyevitch, T., ... Saunthararajah, Y. (2018). Leukemogenic nucleophosmin mutation disrupts the transcription factor hub regulating granulo-monocytic fates. The Journal of clinical investigation, 128(10), 4260-4279. https://doi.org/10.1172/JCI97117

CBE

Gu X, Ebrahem Q, Mahfouz RZ, Hasipek M, Enane F, Radivoyevitch T, Rapin N, Przychodzen B, Hu Z, Balusu R, Cotta CV, Wald D, Argueta C, Landesman Y, Martelli MP, Falini B, Carraway H, Porse BT, Maciejewski JP, Jha BK, Saunthararajah Y. 2018. Leukemogenic nucleophosmin mutation disrupts the transcription factor hub regulating granulo-monocytic fates. The Journal of clinical investigation. 128(10):4260-4279. https://doi.org/10.1172/JCI97117

MLA

Vancouver

Author

Gu, Xiaorong ; Ebrahem, Quteba ; Mahfouz, Reda Z ; Hasipek, Metis ; Enane, Francis ; Radivoyevitch, Tomas ; Rapin, Nicolas ; Przychodzen, Bartlomiej ; Hu, Zhenbo ; Balusu, Ramesh ; Cotta, Claudiu V ; Wald, David ; Argueta, Christian ; Landesman, Yosef ; Martelli, Maria Paola ; Falini, Brunangelo ; Carraway, Hetty ; Porse, Bo T ; Maciejewski, Jaroslaw P ; Jha, Babal K ; Saunthararajah, Yogen. / Leukemogenic nucleophosmin mutation disrupts the transcription factor hub regulating granulo-monocytic fates. In: The Journal of clinical investigation. 2018 ; Vol. 128, No. 10. pp. 4260-4279.

Bibtex

@article{80d624d2948848bba5b0297a93a005bd,
title = "Leukemogenic nucleophosmin mutation disrupts the transcription factor hub regulating granulo-monocytic fates",
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.",
author = "Xiaorong Gu and Quteba Ebrahem and Mahfouz, {Reda Z} and Metis Hasipek and Francis Enane and Tomas Radivoyevitch and Nicolas Rapin and Bartlomiej Przychodzen and Zhenbo Hu and Ramesh Balusu and Cotta, {Claudiu V} and David Wald and Christian Argueta and Yosef Landesman and Martelli, {Maria Paola} and Brunangelo Falini and Hetty Carraway and Porse, {Bo T} and Maciejewski, {Jaroslaw P} and Jha, {Babal K} and Yogen Saunthararajah",
year = "2018",
month = "10",
day = "1",
doi = "10.1172/JCI97117",
language = "English",
volume = "128",
pages = "4260--4279",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "American Society for Clinical Investigation",
number = "10",

}

RIS

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

VL - 128

SP - 4260

EP - 4279

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 10

ER -

ID: 54954225