Disruption of a GATA2, TAL1, ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells.

Thoms, JAI; Truong, P; Subramanian, S; Knezevic, K; Harvey, G; Huang, Y; Seneviratne, JA; Carter, DR; Joshi, S; Skhinas, J; Chacon, D; Shah, A; de Jong, I; Beck, D; Gottgens, B; Larsson, J; Wong, JWH; Zanini, F; Pimanda, JE

Disruption of a GATA2, TAL1, ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells.

Thoms, JAI Truong, P Subramanian, S Knezevic, K Harvey, G Huang, Y

Seneviratne, JA Carter, DR Joshi, S Skhinas, J Chacon, D Shah, A de Jong, I Beck, D Gottgens, B Larsson, J Wong, JWH Zanini, F Pimanda, JE

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Publisher:: American Society of Hematology
Publication Type:: Journal Article
Citation:: Blood, 2021, 138, (16), pp. 1441-1455
Issue Date:: 2021-06-01

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Field	Value	Language
dc.contributor.author	Thoms, JAI
dc.contributor.author	Truong, P
dc.contributor.author	Subramanian, S
dc.contributor.author	Knezevic, K
dc.contributor.author	Harvey, G
dc.contributor.author	Huang, Y https://orcid.org/0000-0002-7003-3110
dc.contributor.author	Seneviratne, JA
dc.contributor.author	Carter, DR
dc.contributor.author	Joshi, S
dc.contributor.author	Skhinas, J
dc.contributor.author	Chacon, D
dc.contributor.author	Shah, A
dc.contributor.author	de Jong, I
dc.contributor.author	Beck, D
dc.contributor.author	Gottgens, B
dc.contributor.author	Larsson, J
dc.contributor.author	Wong, JWH
dc.contributor.author	Zanini, F
dc.contributor.author	Pimanda, JE
dc.date.accessioned	2022-03-08T03:35:01Z
dc.date.available	2021-05-03
dc.date.available	2022-03-08T03:35:01Z
dc.date.issued	2021-06-01
dc.identifier.citation	Blood, 2021, 138, (16), pp. 1441-1455
dc.identifier.issn	0006-4971
dc.identifier.issn	1528-0020
dc.identifier.uri	http://hdl.handle.net/10453/155051
dc.description.abstract	Changes in gene regulation and expression govern orderly transitions from hematopoietic stem cells to terminally differentiated blood cell types. These transitions are disrupted during leukemic transformation, but knowledge of the gene regulatory changes underpinning this process is elusive. We hypothesized that identifying core gene regulatory networks in healthy hematopoietic and leukemic cells could provide insights into network alterations that perturb cell state transitions. A heptad of transcription factors (LYL1, TAL1, LMO2, FLI1, ERG, GATA2, and RUNX1) bind key hematopoietic genes in human CD34+ hematopoietic stem and progenitor cells (HSPCs) and have prognostic significance in acute myeloid leukemia (AML). These factors also form a densely interconnected circuit by binding combinatorially at their own, and each other's, regulatory elements. However, their mutual regulation during normal hematopoiesis and in AML cells, and how perturbation of their expression levels influences cell fate decisions remains unclear. In this study, we integrated bulk and single-cell data and found that the fully connected heptad circuit identified in healthy HSPCs persists, with only minor alterations in AML, and that chromatin accessibility at key heptad regulatory elements was predictive of cell identity in both healthy progenitors and leukemic cells. The heptad factors GATA2, TAL1, and ERG formed an integrated subcircuit that regulates stem cell-to-erythroid transition in both healthy and leukemic cells. Components of this triad could be manipulated to facilitate erythroid transition providing a proof of concept that such regulatory circuits can be harnessed to promote specific cell-type transitions and overcome dysregulated hematopoiesis.
dc.format	Print
dc.language	eng
dc.publisher	American Society of Hematology
dc.relation.ispartof	Blood
dc.relation.isbasedon	10.1182/blood.2020009707
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences, 1114 Paediatrics and Reproductive Medicine
dc.subject.classification	Immunology
dc.subject.mesh	Erythroid Cells
dc.subject.mesh	GATA2 Transcription Factor
dc.subject.mesh	Gene Expression Regulation, Leukemic
dc.subject.mesh	Gene Regulatory Networks
dc.subject.mesh	Hematopoiesis
dc.subject.mesh	Humans
dc.subject.mesh	Leukemia, Myeloid, Acute
dc.subject.mesh	Neoplastic Stem Cells
dc.subject.mesh	T-Cell Acute Lymphocytic Leukemia Protein 1
dc.subject.mesh	Transcriptional Regulator ERG
dc.subject.mesh	Erythroid Cells
dc.subject.mesh	Humans
dc.subject.mesh	Hematopoiesis
dc.subject.mesh	Gene Expression Regulation, Leukemic
dc.subject.mesh	GATA2 Transcription Factor
dc.subject.mesh	Gene Regulatory Networks
dc.subject.mesh	Neoplastic Stem Cells
dc.subject.mesh	Leukemia, Myeloid, Acute
dc.subject.mesh	Transcriptional Regulator ERG
dc.subject.mesh	T-Cell Acute Lymphocytic Leukemia Protein 1
dc.title	Disruption of a GATA2, TAL1, ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells.
dc.type	Journal Article
utslib.citation.volume	138
utslib.location.activity	United States
utslib.for	1102 Cardiorespiratory Medicine and Haematology
utslib.for	1103 Clinical Sciences
utslib.for	1114 Paediatrics and Reproductive Medicine
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
pubs.organisational-group	/University of Technology Sydney/Strength - AAI - Advanced Analytics Institute Research Centre
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
utslib.copyright.status	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2022-03-08T03:34:56Z
pubs.issue	16
pubs.publication-status	Published
pubs.volume	138
utslib.citation.issue	16

Abstract:

Changes in gene regulation and expression govern orderly transitions from hematopoietic stem cells to terminally differentiated blood cell types. These transitions are disrupted during leukemic transformation, but knowledge of the gene regulatory changes underpinning this process is elusive. We hypothesized that identifying core gene regulatory networks in healthy hematopoietic and leukemic cells could provide insights into network alterations that perturb cell state transitions. A heptad of transcription factors (LYL1, TAL1, LMO2, FLI1, ERG, GATA2, and RUNX1) bind key hematopoietic genes in human CD34+ hematopoietic stem and progenitor cells (HSPCs) and have prognostic significance in acute myeloid leukemia (AML). These factors also form a densely interconnected circuit by binding combinatorially at their own, and each other's, regulatory elements. However, their mutual regulation during normal hematopoiesis and in AML cells, and how perturbation of their expression levels influences cell fate decisions remains unclear. In this study, we integrated bulk and single-cell data and found that the fully connected heptad circuit identified in healthy HSPCs persists, with only minor alterations in AML, and that chromatin accessibility at key heptad regulatory elements was predictive of cell identity in both healthy progenitors and leukemic cells. The heptad factors GATA2, TAL1, and ERG formed an integrated subcircuit that regulates stem cell-to-erythroid transition in both healthy and leukemic cells. Components of this triad could be manipulated to facilitate erythroid transition providing a proof of concept that such regulatory circuits can be harnessed to promote specific cell-type transitions and overcome dysregulated hematopoiesis.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/155051