Subtype-specific regulatory network rewiring in acute myeloid leukemia

Salam A Assi; Maria Rosaria Imperato; Daniel J L Coleman; Anna Pickin; Sandeep Potluri; Anetta Ptasinska; Paulynn Suyin Chin; Helen Blair; Pierre Cauchy; Sally R James; Joaquin Zacarias-Cabeza; L Niall Gilding; Andrew Beggs; Sam Clokie; Justin C Loke; Phil Jenkin; Ash Uddin; Ruud Delwel; Stephen J Richards; Manoj Raghavan; Michael J Griffiths; Olaf Heidenreich; Peter N Cockerill; Constanze Bonifer

doi:10.1038/s41588-018-0270-1

Subtype-specific regulatory network rewiring in acute myeloid leukemia

Salam A Assi, Maria Rosaria Imperato, Daniel J L Coleman, Anna Pickin, Sandeep Potluri, Anetta Ptasinska, Paulynn Suyin Chin, Helen Blair, Pierre Cauchy, Sally R James, Joaquin Zacarias-Cabeza, L Niall Gilding, Andrew Beggs, Sam Clokie, Justin C Loke, Phil Jenkin, Ash Uddin, Ruud Delwel, Stephen J Richards, Manoj RaghavanMichael J Griffiths, Olaf Heidenreich, Peter N Cockerill, Constanze Bonifer

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Samenvatting

Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of alterations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype-specific transcriptional networks, we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focused on specific subgroups of subjects carrying mutations in genes encoding transcription factors (RUNX1, CEBPα), signaling molecules (FTL3-ITD, RAS) and the nuclear protein NPM1). Integrated analysis of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance.

Originele taal-2	Engels
Pagina's (van-tot)	151-162
Aantal pagina's	12
Tijdschrift	Nature Genetics
Volume	51
Nummer van het tijdschrift	1
DOI's	https://doi.org/10.1038/s41588-018-0270-1
Status	Gepubliceerd - jan. 2019
Extern gepubliceerd	Ja

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Assi, S. A., Imperato, M. R., Coleman, D. J. L., Pickin, A., Potluri, S., Ptasinska, A., Chin, P. S., Blair, H., Cauchy, P., James, S. R., Zacarias-Cabeza, J., Gilding, L. N., Beggs, A., Clokie, S., Loke, J. C., Jenkin, P., Uddin, A., Delwel, R., Richards, S. J., ... Bonifer, C. (2019). Subtype-specific regulatory network rewiring in acute myeloid leukemia. Nature Genetics, 51(1), 151-162. https://doi.org/10.1038/s41588-018-0270-1

@article{f350e005ff6c43a4907fd993e41c4f71,

title = "Subtype-specific regulatory network rewiring in acute myeloid leukemia",

abstract = "Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of alterations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype-specific transcriptional networks, we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focused on specific subgroups of subjects carrying mutations in genes encoding transcription factors (RUNX1, CEBPα), signaling molecules (FTL3-ITD, RAS) and the nuclear protein NPM1). Integrated analysis of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance.",

keywords = "Adult, Aged, Aged, 80 and over, Female, Gene Expression Regulation, Leukemic/genetics, Gene Regulatory Networks/genetics, Humans, Leukemia, Myeloid, Acute/genetics, Male, Middle Aged, Nucleophosmin, Signal Transduction/genetics, Transcription Factors/genetics, Young Adult",

author = "Assi, {Salam A} and Imperato, {Maria Rosaria} and Coleman, {Daniel J L} and Anna Pickin and Sandeep Potluri and Anetta Ptasinska and Chin, {Paulynn Suyin} and Helen Blair and Pierre Cauchy and James, {Sally R} and Joaquin Zacarias-Cabeza and Gilding, {L Niall} and Andrew Beggs and Sam Clokie and Loke, {Justin C} and Phil Jenkin and Ash Uddin and Ruud Delwel and Richards, {Stephen J} and Manoj Raghavan and Griffiths, {Michael J} and Olaf Heidenreich and Cockerill, {Peter N} and Constanze Bonifer",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2019",

month = jan,

doi = "10.1038/s41588-018-0270-1",

language = "English",

volume = "51",

pages = "151--162",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "1",

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Assi, SA, Imperato, MR, Coleman, DJL, Pickin, A, Potluri, S, Ptasinska, A, Chin, PS, Blair, H, Cauchy, P, James, SR, Zacarias-Cabeza, J, Gilding, LN, Beggs, A, Clokie, S, Loke, JC, Jenkin, P, Uddin, A, Delwel, R, Richards, SJ, Raghavan, M, Griffiths, MJ, Heidenreich, O, Cockerill, PN & Bonifer, C 2019, 'Subtype-specific regulatory network rewiring in acute myeloid leukemia', Nature Genetics, vol. 51, nr. 1, blz. 151-162. https://doi.org/10.1038/s41588-018-0270-1

TY - JOUR

T1 - Subtype-specific regulatory network rewiring in acute myeloid leukemia

AU - Assi, Salam A

AU - Imperato, Maria Rosaria

AU - Coleman, Daniel J L

AU - Pickin, Anna

AU - Potluri, Sandeep

AU - Ptasinska, Anetta

AU - Chin, Paulynn Suyin

AU - Blair, Helen

AU - Cauchy, Pierre

AU - James, Sally R

AU - Zacarias-Cabeza, Joaquin

AU - Gilding, L Niall

AU - Beggs, Andrew

AU - Clokie, Sam

AU - Loke, Justin C

AU - Jenkin, Phil

AU - Uddin, Ash

AU - Delwel, Ruud

AU - Richards, Stephen J

AU - Raghavan, Manoj

AU - Griffiths, Michael J

AU - Heidenreich, Olaf

AU - Cockerill, Peter N

AU - Bonifer, Constanze

PY - 2019/1

Y1 - 2019/1

N2 - Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of alterations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype-specific transcriptional networks, we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focused on specific subgroups of subjects carrying mutations in genes encoding transcription factors (RUNX1, CEBPα), signaling molecules (FTL3-ITD, RAS) and the nuclear protein NPM1). Integrated analysis of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance.

AB - Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of alterations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype-specific transcriptional networks, we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focused on specific subgroups of subjects carrying mutations in genes encoding transcription factors (RUNX1, CEBPα), signaling molecules (FTL3-ITD, RAS) and the nuclear protein NPM1). Integrated analysis of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Female

KW - Gene Expression Regulation, Leukemic/genetics

KW - Gene Regulatory Networks/genetics

KW - Humans

KW - Leukemia, Myeloid, Acute/genetics

KW - Male

KW - Middle Aged

KW - Nucleophosmin

KW - Signal Transduction/genetics

KW - Transcription Factors/genetics

KW - Young Adult

UR - http://www.scopus.com/inward/record.url?scp=85056487218&partnerID=8YFLogxK

U2 - 10.1038/s41588-018-0270-1

DO - 10.1038/s41588-018-0270-1

M3 - Article

C2 - 30420649

SN - 1061-4036

VL - 51

SP - 151

EP - 162

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

Subtype-specific regulatory network rewiring in acute myeloid leukemia

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