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dc.contributor.authorThoms, Julie AIen
dc.contributor.authorTruong, Peteren
dc.contributor.authorSubramanian, Shruthien
dc.contributor.authorKnezevic, Kathyen
dc.contributor.authorHarvey, Gregoryen
dc.contributor.authorHuang, Yizhouen
dc.contributor.authorSeneviratne, Janith Aen
dc.contributor.authorCarter, Daniel Ren
dc.contributor.authorJoshi, Swapnaen
dc.contributor.authorSkhinas, Joannaen
dc.contributor.authorChacon, Diegoen
dc.contributor.authorShah, Anushien
dc.contributor.authorde Jong, Inekeen
dc.contributor.authorBeck, Dominiken
dc.contributor.authorGottgens, Bertholden
dc.contributor.authorLarsson, Jonasen
dc.contributor.authorWong, Jason Wing Honen
dc.contributor.authorZanini, Fabioen
dc.contributor.authorPimanda, John Een
dc.date.accessioned2021-05-05T23:30:25Z
dc.date.available2021-05-05T23:30:25Z
dc.date.issued2021-06en
dc.identifier.issn0006-4971
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/322008
dc.description.abstractChanges 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 hypothesised 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, RUNX1) bind key hematopoietic genes in human CD34+ haematopoietic 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 haematopoiesis and in AML cells, and how perturbation of their expression levels influences cell fate decisions remains unclear. Here, 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 in leukemic cells. The heptad factors GATA2, TAL1 and ERG formed an integrated sub-circuit 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 could be harnessed to promote specific cell type transitions and overcome dysregulated haematopoiesis.
dc.description.sponsorshipWellcome Investigator award (206328/Z/17/Z)
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherAmerican Society of Hematology
dc.rightsAll rights reserved
dc.titleDisruption of a GATA2, TAL1, ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells.en
dc.typeArticle
prism.publicationDate2021en
prism.publicationNameBlooden
dc.identifier.doi10.17863/CAM.69466
dcterms.dateAccepted2021-05-03en
rioxxterms.versionofrecord10.1182/blood.2020009707en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2021-06en
dc.contributor.orcidThoms, Julie AI [0000-0002-4876-7230]
dc.contributor.orcidHuang, Yizhou [0000-0002-7003-3110]
dc.contributor.orcidSeneviratne, Janith A [0000-0003-0413-5829]
dc.contributor.orcidGottgens, Berthold [0000-0001-6302-5705]
dc.contributor.orcidZanini, Fabio [0000-0001-7097-8539]
dc.identifier.eissn1528-0020
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (206328/Z/17/Z)
cam.orpheus.successMon Jun 07 07:30:49 BST 2021 - Embargo updated*
cam.orpheus.counter4*
rioxxterms.freetoread.startdate2022-06-30


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