Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth

Daniel J L Coleman; Peter Keane; Rosario Luque-Martin; Paulynn S Chin; Helen Blair; Luke Ames; Sophie G Kellaway; James Griffin; Elizabeth Holmes; Sandeep Potluri; Salam A Assi; John Bushweller; Olaf Heidenreich; Peter N Cockerill; Constanze Bonifer

doi:10.1016/j.celrep.2023.113568

Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth

Daniel J L Coleman, Peter Keane, Rosario Luque-Martin, Paulynn S Chin, Helen Blair, Luke Ames, Sophie G Kellaway, James Griffin, Elizabeth Holmes, Sandeep Potluri, Salam A Assi, John Bushweller, Olaf Heidenreich^*, Peter N Cockerill^*, Constanze Bonifer^*

^*Corresponding author for this work

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

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Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease caused by different mutations. Previously, we showed that each mutational subtype develops its specific gene regulatory network (GRN) with transcription factors interacting within multiple gene modules, many of which are transcription factor genes themselves. Here, we hypothesize that highly connected nodes within such networks comprise crucial regulators of AML maintenance. We test this hypothesis using FLT3-ITD-mutated AML as a model and conduct an shRNA drop-out screen informed by this analysis. We show that AML-specific GRNs predict crucial regulatory modules required for AML growth. Furthermore, our work shows that all modules are highly connected and regulate each other. The careful multi-omic analysis of the role of one (RUNX1) module by shRNA and chemical inhibition shows that this transcription factor and its target genes stabilize the GRN of FLT3-ITD+ AML and that its removal leads to GRN collapse and cell death.

Original language	English
Article number	113568
Journal	Cell Reports
Volume	42
Issue number	12
Early online date	15 Dec 2023
DOIs	https://doi.org/10.1016/j.celrep.2023.113568
Publication status	Published - 26 Dec 2023

Bibliographical note

Acknowledgments
We are grateful to the Genomics Birmingham Facility and to the University of Birmingham Flow Cytometry platform for their expert services. This work as funded by a grant from the Medical Research Council UK to C.B., O.H., and P.N.C. (MR/S021469/1), by a grant from Blood Cancer UK to C.B. and P.N.C. (15001), and by a grant from the National Institutes of Health to J.B. (R01 CA234478). D.J.L.C. is a John Goldman Fellow of Leukemia UK (2021/JGF/001).

Copyright © 2023 The Authors.

Keywords

Humans
Gene Regulatory Networks
Regulon
Leukemia, Myeloid, Acute/genetics
Mutation/genetics
RNA, Small Interfering
fms-Like Tyrosine Kinase 3/genetics

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10.1016/j.celrep.2023.113568Licence: Creative Commons: Attribution (CC BY)

ColemanDJL2023GeneFinal published version, 6.91 MBLicence: Creative Commons: Attribution (CC BY)

Pharmaceutical targeting of RAS in Acute Myeloid Leukaemia with RAS mutations or FLT3-ITD
Coleman, D. (Principal Investigator)
LEUKAEMIA UK
1/01/22 → 29/02/24
Project: Research
Finding therapeutic targets in FLT3-ITD AML using a systems biology approach
Cockerill, P. (Co-Investigator) & Bonifer, C. (Principal Investigator)
Medical Research Council
1/09/19 → 31/12/23
Project: Research Councils

Cite this

Coleman, D. J. L., Keane, P., Luque-Martin, R., Chin, P. S., Blair, H., Ames, L., Kellaway, S. G., Griffin, J., Holmes, E., Potluri, S., Assi, S. A., Bushweller, J., Heidenreich, O., Cockerill, P. N., & Bonifer, C. (2023). Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth. Cell Reports, 42(12), Article 113568. https://doi.org/10.1016/j.celrep.2023.113568

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title = "Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth",

abstract = "Acute myeloid leukemia (AML) is a heterogeneous disease caused by different mutations. Previously, we showed that each mutational subtype develops its specific gene regulatory network (GRN) with transcription factors interacting within multiple gene modules, many of which are transcription factor genes themselves. Here, we hypothesize that highly connected nodes within such networks comprise crucial regulators of AML maintenance. We test this hypothesis using FLT3-ITD-mutated AML as a model and conduct an shRNA drop-out screen informed by this analysis. We show that AML-specific GRNs predict crucial regulatory modules required for AML growth. Furthermore, our work shows that all modules are highly connected and regulate each other. The careful multi-omic analysis of the role of one (RUNX1) module by shRNA and chemical inhibition shows that this transcription factor and its target genes stabilize the GRN of FLT3-ITD+ AML and that its removal leads to GRN collapse and cell death.",

keywords = "Humans, Gene Regulatory Networks, Regulon, Leukemia, Myeloid, Acute/genetics, Mutation/genetics, RNA, Small Interfering, fms-Like Tyrosine Kinase 3/genetics",

author = "Coleman, {Daniel J L} and Peter Keane and Rosario Luque-Martin and Chin, {Paulynn S} and Helen Blair and Luke Ames and Kellaway, {Sophie G} and James Griffin and Elizabeth Holmes and Sandeep Potluri and Assi, {Salam A} and John Bushweller and Olaf Heidenreich and Cockerill, {Peter N} and Constanze Bonifer",

note = "Acknowledgments We are grateful to the Genomics Birmingham Facility and to the University of Birmingham Flow Cytometry platform for their expert services. This work as funded by a grant from the Medical Research Council UK to C.B., O.H., and P.N.C. (MR/S021469/1), by a grant from Blood Cancer UK to C.B. and P.N.C. (15001), and by a grant from the National Institutes of Health to J.B. (R01 CA234478). D.J.L.C. is a John Goldman Fellow of Leukemia UK (2021/JGF/001). Copyright {\textcopyright} 2023 The Authors. ",

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Coleman, DJL, Keane, P, Luque-Martin, R, Chin, PS, Blair, H, Ames, L, Kellaway, SG, Griffin, J, Holmes, E, Potluri, S, Assi, SA, Bushweller, J, Heidenreich, O, Cockerill, PN & Bonifer, C 2023, 'Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth', Cell Reports, vol. 42, no. 12, 113568. https://doi.org/10.1016/j.celrep.2023.113568

TY - JOUR

T1 - Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth

AU - Coleman, Daniel J L

AU - Keane, Peter

AU - Luque-Martin, Rosario

AU - Chin, Paulynn S

AU - Blair, Helen

AU - Ames, Luke

AU - Kellaway, Sophie G

AU - Griffin, James

AU - Holmes, Elizabeth

AU - Potluri, Sandeep

AU - Assi, Salam A

AU - Bushweller, John

AU - Heidenreich, Olaf

AU - Cockerill, Peter N

AU - Bonifer, Constanze

N1 - Acknowledgments We are grateful to the Genomics Birmingham Facility and to the University of Birmingham Flow Cytometry platform for their expert services. This work as funded by a grant from the Medical Research Council UK to C.B., O.H., and P.N.C. (MR/S021469/1), by a grant from Blood Cancer UK to C.B. and P.N.C. (15001), and by a grant from the National Institutes of Health to J.B. (R01 CA234478). D.J.L.C. is a John Goldman Fellow of Leukemia UK (2021/JGF/001). Copyright © 2023 The Authors.

PY - 2023/12/26

Y1 - 2023/12/26

N2 - Acute myeloid leukemia (AML) is a heterogeneous disease caused by different mutations. Previously, we showed that each mutational subtype develops its specific gene regulatory network (GRN) with transcription factors interacting within multiple gene modules, many of which are transcription factor genes themselves. Here, we hypothesize that highly connected nodes within such networks comprise crucial regulators of AML maintenance. We test this hypothesis using FLT3-ITD-mutated AML as a model and conduct an shRNA drop-out screen informed by this analysis. We show that AML-specific GRNs predict crucial regulatory modules required for AML growth. Furthermore, our work shows that all modules are highly connected and regulate each other. The careful multi-omic analysis of the role of one (RUNX1) module by shRNA and chemical inhibition shows that this transcription factor and its target genes stabilize the GRN of FLT3-ITD+ AML and that its removal leads to GRN collapse and cell death.

AB - Acute myeloid leukemia (AML) is a heterogeneous disease caused by different mutations. Previously, we showed that each mutational subtype develops its specific gene regulatory network (GRN) with transcription factors interacting within multiple gene modules, many of which are transcription factor genes themselves. Here, we hypothesize that highly connected nodes within such networks comprise crucial regulators of AML maintenance. We test this hypothesis using FLT3-ITD-mutated AML as a model and conduct an shRNA drop-out screen informed by this analysis. We show that AML-specific GRNs predict crucial regulatory modules required for AML growth. Furthermore, our work shows that all modules are highly connected and regulate each other. The careful multi-omic analysis of the role of one (RUNX1) module by shRNA and chemical inhibition shows that this transcription factor and its target genes stabilize the GRN of FLT3-ITD+ AML and that its removal leads to GRN collapse and cell death.

KW - Humans

KW - Gene Regulatory Networks

KW - Regulon

KW - Leukemia, Myeloid, Acute/genetics

KW - Mutation/genetics

KW - RNA, Small Interfering

KW - fms-Like Tyrosine Kinase 3/genetics

U2 - 10.1016/j.celrep.2023.113568

DO - 10.1016/j.celrep.2023.113568

M3 - Article

C2 - 38104314

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 12

M1 - 113568

ER -

Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth

Abstract

Bibliographical note

Keywords

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Projects

Pharmaceutical targeting of RAS in Acute Myeloid Leukaemia with RAS mutations or FLT3-ITD

Finding therapeutic targets in FLT3-ITD AML using a systems biology approach

Cite this