Chronic FLT3-ITD Signaling in Acute Myeloid Leukemia Is Connected to a Specific Chromatin Signature

Pierre Cauchy; Sally R. James; Joaquin Zacarias Cabeza; Anetta Ptasinska; Maria Imperato; Salam A. Assi; Jason Piper; Martina Canestraro; Maarten Hoogenkamp; Manoj Raghavan; Justin Loke; Susanna Akiki; Samuel J. Clokie; Stephen J. Richards; David R. Westhead; Michael Griffiths; Sascha Ott; Constanze Bonifer; Peter Cockerill

doi:10.1016/j.celrep.2015.06.069

Chronic FLT3-ITD Signaling in Acute Myeloid Leukemia Is Connected to a Specific Chromatin Signature

Pierre Cauchy, Sally R. James, Joaquin Zacarias Cabeza, Anetta Ptasinska, Maria Imperato, Salam A. Assi, Jason Piper, Martina Canestraro, Maarten Hoogenkamp, Manoj Raghavan, Justin Loke, Susanna Akiki, Samuel J. Clokie, Stephen J. Richards, David R. Westhead, Michael Griffiths, Sascha Ott, Constanze Bonifer^*, Peter Cockerill

^*Corresponding author for this work

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

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Abstract

Acute myeloid leukemia (AML) is characterized by recurrent mutations that affect the epigenetic regulatory machinery and signaling molecules, leading to a block in hematopoietic differentiation. Constitutive signaling from mutated growth factor receptors is a major driver of leukemic growth, but how aberrant signaling affects the epigenome in AML is less understood. Furthermore, AML cells undergo extensive clonal evolution, and the mutations in signaling genes are often secondary events. To elucidate how chronic growth factor signaling alters the transcriptional network in AML, we performed a system-wide multi-omics study of primary cells from patients suffering from AML with internal tandem duplications in the FLT3 transmembrane domain (FLT3-ITD). This strategy revealed cooperation between the MAP kinase (MAPK) inducible transcription factor AP-1 and RUNX1 as a major driver of a common, FLT3-ITD-specific gene expression and chromatin signature, demonstrating a major impact of MAPK signaling pathways in shaping the epigenome of FLT3-ITD AML.

Original language	English
Pages (from-to)	821-836
Number of pages	16
Journal	Cell Reports
Volume	12
Issue number	5
Early online date	23 Jul 2015
DOIs	https://doi.org/10.1016/j.celrep.2015.06.069
Publication status	Published - 4 Aug 2015

Bibliographical note

Keywords

acute myeloid leukaemia

ASJC Scopus subject areas

General Medicine
General Immunology and Microbiology

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CauchyP2015Chronic
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Mechanistic Insights into the Interplay Between Transcription Factors and the Epigenetic Regulatory Machinery in Normal and Leukaemic Cells
Bonifer, C. (Principal Investigator) & Cockerill, P. (Co-Investigator)
BLOODWISE
1/07/12 → 31/03/17
Project: Research

Cite this

Cauchy, P., James, S. R., Zacarias Cabeza, J., Ptasinska, A., Imperato, M., Assi, S. A., Piper, J., Canestraro, M., Hoogenkamp, M., Raghavan, M., Loke, J., Akiki, S., Clokie, S. J., Richards, S. J., Westhead, D. R., Griffiths, M., Ott, S., Bonifer, C., & Cockerill, P. (2015). Chronic FLT3-ITD Signaling in Acute Myeloid Leukemia Is Connected to a Specific Chromatin Signature. Cell Reports, 12(5), 821-836. https://doi.org/10.1016/j.celrep.2015.06.069

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title = "Chronic FLT3-ITD Signaling in Acute Myeloid Leukemia Is Connected to a Specific Chromatin Signature",

abstract = "Acute myeloid leukemia (AML) is characterized by recurrent mutations that affect the epigenetic regulatory machinery and signaling molecules, leading to a block in hematopoietic differentiation. Constitutive signaling from mutated growth factor receptors is a major driver of leukemic growth, but how aberrant signaling affects the epigenome in AML is less understood. Furthermore, AML cells undergo extensive clonal evolution, and the mutations in signaling genes are often secondary events. To elucidate how chronic growth factor signaling alters the transcriptional network in AML, we performed a system-wide multi-omics study of primary cells from patients suffering from AML with internal tandem duplications in the FLT3 transmembrane domain (FLT3-ITD). This strategy revealed cooperation between the MAP kinase (MAPK) inducible transcription factor AP-1 and RUNX1 as a major driver of a common, FLT3-ITD-specific gene expression and chromatin signature, demonstrating a major impact of MAPK signaling pathways in shaping the epigenome of FLT3-ITD AML.",

keywords = "acute myeloid leukaemia",

author = "Pierre Cauchy and James, {Sally R.} and {Zacarias Cabeza}, Joaquin and Anetta Ptasinska and Maria Imperato and Assi, {Salam A.} and Jason Piper and Martina Canestraro and Maarten Hoogenkamp and Manoj Raghavan and Justin Loke and Susanna Akiki and Clokie, {Samuel J.} and Richards, {Stephen J.} and Westhead, {David R.} and Michael Griffiths and Sascha Ott and Constanze Bonifer and Peter Cockerill",

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Cauchy, P, James, SR, Zacarias Cabeza, J, Ptasinska, A, Imperato, M, Assi, SA, Piper, J, Canestraro, M, Hoogenkamp, M , Raghavan, M , Loke, J, Akiki, S, Clokie, SJ, Richards, SJ, Westhead, DR, Griffiths, M, Ott, S, Bonifer, C & Cockerill, P 2015, 'Chronic FLT3-ITD Signaling in Acute Myeloid Leukemia Is Connected to a Specific Chromatin Signature', Cell Reports, vol. 12, no. 5, pp. 821-836. https://doi.org/10.1016/j.celrep.2015.06.069

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AU - Ptasinska, Anetta

AU - Imperato, Maria

AU - Assi, Salam A.

AU - Piper, Jason

AU - Canestraro, Martina

AU - Hoogenkamp, Maarten

AU - Raghavan, Manoj

AU - Loke, Justin

AU - Akiki, Susanna

AU - Clokie, Samuel J.

AU - Richards, Stephen J.

AU - Westhead, David R.

AU - Griffiths, Michael

AU - Ott, Sascha

AU - Bonifer, Constanze

AU - Cockerill, Peter

PY - 2015/8/4

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N2 - Acute myeloid leukemia (AML) is characterized by recurrent mutations that affect the epigenetic regulatory machinery and signaling molecules, leading to a block in hematopoietic differentiation. Constitutive signaling from mutated growth factor receptors is a major driver of leukemic growth, but how aberrant signaling affects the epigenome in AML is less understood. Furthermore, AML cells undergo extensive clonal evolution, and the mutations in signaling genes are often secondary events. To elucidate how chronic growth factor signaling alters the transcriptional network in AML, we performed a system-wide multi-omics study of primary cells from patients suffering from AML with internal tandem duplications in the FLT3 transmembrane domain (FLT3-ITD). This strategy revealed cooperation between the MAP kinase (MAPK) inducible transcription factor AP-1 and RUNX1 as a major driver of a common, FLT3-ITD-specific gene expression and chromatin signature, demonstrating a major impact of MAPK signaling pathways in shaping the epigenome of FLT3-ITD AML.

AB - Acute myeloid leukemia (AML) is characterized by recurrent mutations that affect the epigenetic regulatory machinery and signaling molecules, leading to a block in hematopoietic differentiation. Constitutive signaling from mutated growth factor receptors is a major driver of leukemic growth, but how aberrant signaling affects the epigenome in AML is less understood. Furthermore, AML cells undergo extensive clonal evolution, and the mutations in signaling genes are often secondary events. To elucidate how chronic growth factor signaling alters the transcriptional network in AML, we performed a system-wide multi-omics study of primary cells from patients suffering from AML with internal tandem duplications in the FLT3 transmembrane domain (FLT3-ITD). This strategy revealed cooperation between the MAP kinase (MAPK) inducible transcription factor AP-1 and RUNX1 as a major driver of a common, FLT3-ITD-specific gene expression and chromatin signature, demonstrating a major impact of MAPK signaling pathways in shaping the epigenome of FLT3-ITD AML.

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Chronic FLT3-ITD Signaling in Acute Myeloid Leukemia Is Connected to a Specific Chromatin Signature

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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Mechanistic Insights into the Interplay Between Transcription Factors and the Epigenetic Regulatory Machinery in Normal and Leukaemic Cells

Cite this