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

Research output: Contribution to journal › Article › peer-review

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. Using in vitro and in vivo screens to identify essential RUNX1/ETO transcriptional targets in AML, Martinez-Soria identify CCND2 as required for leukemia maintenance and self-renewal. Targeting this dependency using the CDK4/6 inhibitor palbociclib prolongs the survival of AML PDX models.

Original language	English
Pages (from-to)	705
Journal	Cancer Cell
Volume	34
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2018.08.015 https://doi.org/10.1016/j.ccell.2019.03.012
Publication status	Published - 8 Oct 2018

Keywords

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

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

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

Access to Document

Cite this

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), 705. https://doi.org/10.1016/j.ccell.2018.08.015, https://doi.org/10.1016/j.ccell.2019.03.012

@article{c8ac0ff2d9af420faa3b957c35c55420,

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. Using in vitro and in vivo screens to identify essential RUNX1/ETO transcriptional targets in AML, Martinez-Soria identify CCND2 as required for leukemia maintenance and self-renewal. Targeting this dependency using the CDK4/6 inhibitor palbociclib prolongs the survival of AML PDX models.",

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

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 = "705",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "4",

}

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. 705. https://doi.org/10.1016/j.ccell.2018.08.015, https://doi.org/10.1016/j.ccell.2019.03.012

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. Using in vitro and in vivo screens to identify essential RUNX1/ETO transcriptional targets in AML, Martinez-Soria identify CCND2 as required for leukemia maintenance and self-renewal. Targeting this dependency using the CDK4/6 inhibitor palbociclib prolongs the survival of AML PDX models.

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. Using in vitro and in vivo screens to identify essential RUNX1/ETO transcriptional targets in AML, Martinez-Soria identify CCND2 as required for leukemia maintenance and self-renewal. Targeting this dependency using the CDK4/6 inhibitor palbociclib prolongs the survival of AML PDX models.

KW - acute myeloid leukemia

KW - CCND2

KW - CDK6 inhibition

KW - cell-cycle control

KW - fusion gene

KW - imatinib

KW - KIT mutation

KW - palbociclib

KW - RNAi screen

KW - RUNX1/ETO

U2 - 10.1016/j.ccell.2018.08.015

DO - 10.1016/j.ccell.2018.08.015

M3 - Article

C2 - 30991028

AN - SCOPUS:85053713785

SN - 1535-6108

VL - 34

SP - 705

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

Research Beacons, Institutes and Platforms

UN SDGs

Access to Document

Fingerprint

Cite this