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; 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, Alex ElderSimon N Bomken, Deepali Pal, James M Allan, Gareth J Veal, Peter N Cockerill, Christian Wichmann, Josef Vormoor, Georges Lacaud, Constanze Bonifer^*, Olaf Heidenreich^*

^*Corresponding author for this work

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

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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	17
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
Externally published	Yes

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Martinez-Soria et al - The Oncogenic Transcription Factor RUNX1-ETO OAFinal published version, 5.54 MBLicence: 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{232ef34c5a8f48a9a44eb0185b75fa2a,

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 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",

note = "Research funded by Bloodwise (150051205515001) | North of England Children{\textquoteright}s Cancer Research Fund | Wellcome Trust (087961) | CRUK program (A12788C27943)",

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 = "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, 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 - 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

N1 - Research funded by Bloodwise (150051205515001) | North of England Children’s Cancer Research Fund | Wellcome Trust (087961) | CRUK program (A12788C27943)

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

VL - 34

SP - 626-642.e8

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 4

ER -

The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation

Abstract

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