Disruption of a GATA2-TAL1-ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells
(2021) In Blood 138(16). p.1441-1455- 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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Blood
- volume
- 138
- issue
- 16
- pages
- 15 pages
- publisher
- American Society of Hematology
- external identifiers
-
- pmid:34075404
- scopus:85117375305
- ISSN
- 0006-4971
- DOI
- 10.1182/blood.2020009707
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2021 American Society of Hematology
- id
- 9b756d87-a707-42e5-8d33-ee99c10fb51d
- date added to LUP
- 2021-11-22 09:36:06
- date last changed
- 2024-07-13 23:12:52
@article{9b756d87-a707-42e5-8d33-ee99c10fb51d,
abstract = {{<p>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<sup>+</sup> 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.</p>}},
author = {{Thoms, Julie A.I. and Truong, Peter and Subramanian, Shruthi and Knezevic, Kathy and Harvey, Gregory and Huang, Yizhou and Seneviratne, Janith A. and Carter, Daniel R. and Joshi, Swapna and Skhinas, Joanna and Chacon, Diego and Shah, Anushi and de Jong, Ineke and Beck, Dominik and Göttgens, Berthold and Larsson, Jonas and Wong, Jason W.H. and Zanini, Fabio and Pimanda, John E.}},
issn = {{0006-4971}},
language = {{eng}},
number = {{16}},
pages = {{1441--1455}},
publisher = {{American Society of Hematology}},
series = {{Blood}},
title = {{Disruption of a GATA2-TAL1-ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells}},
url = {{http://dx.doi.org/10.1182/blood.2020009707}},
doi = {{10.1182/blood.2020009707}},
volume = {{138}},
year = {{2021}},
}