The oncogenic transcription factor RUNX1/ETO corrupts cell cycle regulation to drive leukemic transformation

Natalia Martinez-Soria; Lynsey McKenzie; Julia Draper; Anetta Ptasinska; Hasan Issa; Sandeep Potluri; Helen J Blair; Anna Pickin; Asmida Isa; Paulynn Suyin Chin; Ricky Tirtakusuma; Daniel Coleman; Sirintra Nakjang; Salam Assi; Victoria Forster; Mojgan Reza; Ed Law; Philip Berry; Dorothee Mueller; Cameron  Osborne; Alex Elder; Simon N Bomken; Deepali Pal; James M Allan; Gareth J Veal; Peter N Cockerill; Christian Wichmann; Josef Vormoor; Georges Lacaud; Constanze Bonifer; Olaf Heidenreich

doi:10.1016/j.ccell.2018.08.015

The oncogenic transcription factor RUNX1/ETO corrupts cell cycle regulation to drive leukemic transformation

Natalia Martinez-Soria, Lynsey McKenzie, Julia Draper, Anetta Ptasinska, Hasan Issa, Sandeep Potluri, Helen J Blair, Anna Pickin, Asmida Isa, Paulynn Suyin Chin, Ricky Tirtakusuma, Daniel Coleman, Sirintra Nakjang, Salam Assi, Victoria Forster, Mojgan Reza, Ed Law, Philip Berry, Dorothee Mueller, Cameron OsborneAlex Elder, Simon N Bomken, Deepali Pal, James M Allan, Gareth J Veal, Peter N Cockerill, Christian Wichmann, Josef Vormoor, Georges Lacaud, Constanze Bonifer, Olaf Heidenreich

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Abstract

Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO cooperates with AP-1 to drive CCND2 expression. Knockdown or pharmacological inhibition of CCND2 by an approved drug significantly impairs leukemic expansion of patient-derived AML cells and engraftment in immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO maintains leukemia by promoting cell cycle progression and identifies G1 CCND-CDK complexes as promising therapeutic targets for treatment of RUNX1/ETO-driven AML.

Original language	English
Pages (from-to)	626-642.e8
Number of pages	25
Journal	Cancer Cell
Volume	34
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2018.08.015
Publication status	Published - 8 Oct 2018

Keywords

RNAi screen
fusion gene
cell-cycle control
CDK6 inhibition
RUNX1/ETO
CCND2
acute myeloid leukemia
palbociclib
KIT mutation
imatinib

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Martinez-Soria_et_al_The_oncogenic_transcription_factor_Cancer_Call_2018
Published in Cancel Cell https://doi.org/10.1016/j.ccell.2018.08.015
Final published version, 5.54 MBLicence: Creative Commons: Attribution (CC BY)

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Martinez-Soria, N., McKenzie, L., Draper, J., Ptasinska, A., Issa, H., Potluri, S., Blair, H. J., Pickin, A., Isa, A., Chin, P. S., Tirtakusuma, R., Coleman, D., Nakjang, S., Assi, S., Forster, V., Reza, M., Law, E., Berry, P., Mueller, D., ... Heidenreich, O. (2018). The oncogenic transcription factor RUNX1/ETO corrupts cell cycle regulation to drive leukemic transformation. Cancer Cell, 34(4), 626-642.e8. https://doi.org/10.1016/j.ccell.2018.08.015

@article{b34a9d17bc0746d3b45118ccc768e1b8,

title = "The oncogenic transcription factor RUNX1/ETO corrupts cell cycle regulation to drive leukemic transformation",

abstract = "Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO cooperates with AP-1 to drive CCND2 expression. Knockdown or pharmacological inhibition of CCND2 by an approved drug significantly impairs leukemic expansion of patient-derived AML cells and engraftment in immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO maintains leukemia by promoting cell cycle progression and identifies G1 CCND-CDK complexes as promising therapeutic targets for treatment of RUNX1/ETO-driven AML.",

keywords = "RNAi screen, fusion gene, cell-cycle control, CDK6 inhibition, RUNX1/ETO, CCND2, acute myeloid leukemia, palbociclib, KIT mutation, imatinib",

author = "Natalia Martinez-Soria and Lynsey McKenzie and Julia Draper and Anetta Ptasinska and Hasan Issa and Sandeep Potluri and Blair, {Helen J} and Anna Pickin and Asmida Isa and Chin, {Paulynn Suyin} and Ricky Tirtakusuma and Daniel Coleman and Sirintra Nakjang and Salam Assi and Victoria Forster and Mojgan Reza and Ed Law and Philip Berry and Dorothee Mueller and Cameron Osborne and Alex Elder and Bomken, {Simon N} and Deepali Pal and Allan, {James M} and Veal, {Gareth J} and Cockerill, {Peter N} and Christian Wichmann and Josef Vormoor and Georges Lacaud and Constanze Bonifer and Olaf Heidenreich",

year = "2018",

month = oct,

day = "8",

doi = "10.1016/j.ccell.2018.08.015",

language = "English",

volume = "34",

pages = "626--642.e8",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Elsevier",

number = "4",

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Martinez-Soria, N, McKenzie, L, Draper, J, Ptasinska, A, Issa, H, Potluri, S, Blair, HJ, Pickin, A, Isa, A, Chin, PS, Tirtakusuma, R, Coleman, D, Nakjang, S, Assi, S, Forster, V, Reza, M, Law, E, Berry, P, Mueller, D, Osborne, C, Elder, A, Bomken, SN, Pal, D, Allan, JM, Veal, GJ, Cockerill, PN, Wichmann, C, Vormoor, J, Lacaud, G, Bonifer, C & Heidenreich, O 2018, 'The oncogenic transcription factor RUNX1/ETO corrupts cell cycle regulation to drive leukemic transformation', Cancer Cell, vol. 34, no. 4, pp. 626-642.e8. https://doi.org/10.1016/j.ccell.2018.08.015

TY - JOUR

T1 - The oncogenic transcription factor RUNX1/ETO corrupts cell cycle regulation to drive leukemic transformation

AU - Martinez-Soria, Natalia

AU - McKenzie, Lynsey

AU - Draper, Julia

AU - Ptasinska, Anetta

AU - Issa, Hasan

AU - Potluri, Sandeep

AU - Blair, Helen J

AU - Pickin, Anna

AU - Isa, Asmida

AU - Chin, Paulynn Suyin

AU - Tirtakusuma, Ricky

AU - Coleman, Daniel

AU - Nakjang, Sirintra

AU - Assi, Salam

AU - Forster, Victoria

AU - Reza, Mojgan

AU - Law, Ed

AU - Berry, Philip

AU - Mueller, Dorothee

AU - Osborne, Cameron

AU - Elder, Alex

AU - Bomken, Simon N

AU - Pal, Deepali

AU - Allan, James M

AU - Veal, Gareth J

AU - Cockerill, Peter N

AU - Wichmann, Christian

AU - Vormoor, Josef

AU - Lacaud, Georges

AU - Bonifer, Constanze

AU - Heidenreich, Olaf

PY - 2018/10/8

Y1 - 2018/10/8

N2 - Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO cooperates with AP-1 to drive CCND2 expression. Knockdown or pharmacological inhibition of CCND2 by an approved drug significantly impairs leukemic expansion of patient-derived AML cells and engraftment in immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO maintains leukemia by promoting cell cycle progression and identifies G1 CCND-CDK complexes as promising therapeutic targets for treatment of RUNX1/ETO-driven AML.

AB - Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO cooperates with AP-1 to drive CCND2 expression. Knockdown or pharmacological inhibition of CCND2 by an approved drug significantly impairs leukemic expansion of patient-derived AML cells and engraftment in immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO maintains leukemia by promoting cell cycle progression and identifies G1 CCND-CDK complexes as promising therapeutic targets for treatment of RUNX1/ETO-driven AML.

KW - RNAi screen

KW - fusion gene

KW - cell-cycle control

KW - CDK6 inhibition

KW - RUNX1/ETO

KW - CCND2

KW - acute myeloid leukemia

KW - palbociclib

KW - KIT mutation

KW - imatinib

U2 - 10.1016/j.ccell.2018.08.015

DO - 10.1016/j.ccell.2018.08.015

M3 - Article

C2 - 30300583

SN - 1535-6108

VL - 34

SP - 626-642.e8

JO - Cancer Cell

JF - Cancer Cell

IS - 4

ER -

The oncogenic transcription factor RUNX1/ETO corrupts cell cycle regulation to drive leukemic transformation

Abstract

Keywords

UN SDGs

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Birmingham Environment for Academic Research (BEAR)

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