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.2019.03.012

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

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

87 Citations (Scopus)

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
Journal	Cancer cell
Volume	34
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2019.03.012 https://doi.org/10.1016/j.ccell.2018.08.015
Publication status	Published - 8 Oct 2018
Externally published	Yes

Keywords

Animals
Cell Cycle Checkpoints/genetics
Cell Line, Tumor
Chromosomes, Human, Pair 21/genetics
Core Binding Factor Alpha 2 Subunit/genetics
Cyclin D2/genetics
Gene Expression Regulation, Leukemic/genetics
Humans
Leukemia, Myeloid, Acute/genetics
Male
Mice
Oncogene Proteins, Fusion/genetics
Oncogenes/genetics
Translocation, Genetic/genetics

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), 626-642.e8. https://doi.org/10.1016/j.ccell.2019.03.012, https://doi.org/10.1016/j.ccell.2018.08.015

@article{43c7e058ee4540f0ad6f09935f6b9583,

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 = "Animals, Cell Cycle Checkpoints/genetics, Cell Line, Tumor, Chromosomes, Human, Pair 21/genetics, Core Binding Factor Alpha 2 Subunit/genetics, Cyclin D2/genetics, Gene Expression Regulation, Leukemic/genetics, Humans, Leukemia, Myeloid, Acute/genetics, Male, Mice, Oncogene Proteins, Fusion/genetics, Oncogenes/genetics, Translocation, Genetic/genetics",

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.2019.03.012",

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, 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.2019.03.012, 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 - Animals

KW - Cell Cycle Checkpoints/genetics

KW - Cell Line, Tumor

KW - Chromosomes, Human, Pair 21/genetics

KW - Core Binding Factor Alpha 2 Subunit/genetics

KW - Cyclin D2/genetics

KW - Gene Expression Regulation, Leukemic/genetics

KW - Humans

KW - Leukemia, Myeloid, Acute/genetics

KW - Male

KW - Mice

KW - Oncogene Proteins, Fusion/genetics

KW - Oncogenes/genetics

KW - Translocation, Genetic/genetics

UR - https://www.scopus.com/pages/publications/85053713785

U2 - 10.1016/j.ccell.2019.03.012

DO - 10.1016/j.ccell.2019.03.012

M3 - Article

C2 - 30991028

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

Access to Document

Fingerprint

Cite this