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Single-cell approaches identify the molecular network driving malignant hematopoietic stem cell self-renewal.

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cam.issuedOnline2018-07-10
dc.contributor.authorShepherd, Mairi S
dc.contributor.authorLi, Juan
dc.contributor.authorWilson, Nicola K
dc.contributor.authorOedekoven, Caroline A
dc.contributor.authorLi, Jiangbing
dc.contributor.authorBelmonte, Miriam
dc.contributor.authorFink, Juergen
dc.contributor.authorPrick, Janine CM
dc.contributor.authorPask, Dean C
dc.contributor.authorHamilton, Tina L
dc.contributor.authorLoeffler, Dirk
dc.contributor.authorRao, Anjana
dc.contributor.authorSchröder, Timm
dc.contributor.authorGöttgens, Berthold
dc.contributor.authorGreen, Anthony R
dc.contributor.authorKent, David G
dc.contributor.orcidShepherd, Mairi S [0000-0002-4328-9882]
dc.contributor.orcidWilson, Nicola K [0000-0003-0865-7333]
dc.contributor.orcidOedekoven, Caroline A [0000-0002-2309-2097]
dc.contributor.orcidSchröder, Timm [0000-0001-9320-0252]
dc.contributor.orcidGöttgens, Berthold [0000-0001-6302-5705]
dc.contributor.orcidGreen, Anthony R [0000-0002-9795-0218]
dc.contributor.orcidKent, David G [0000-0001-7871-8811]
dc.date.accessioned2018-11-01T14:01:40Z
dc.date.available2018-11-01T14:01:40Z
dc.date.issued2018-08-23
dc.description.abstractRecent advances in single-cell technologies have permitted the investigation of heterogeneous cell populations at previously unattainable resolution. Here we apply such approaches to resolve the molecular mechanisms driving disease in mouse hematopoietic stem cells (HSCs), using JAK2V617F mutant myeloproliferative neoplasms (MPNs) as a model. Single-cell gene expression and functional assays identified a subset of JAK2V617F mutant HSCs that display defective self-renewal. This defect is rescued at the single HSC level by crossing JAK2V617F mice with mice lacking TET2, the most commonly comutated gene in patients with MPN. Single-cell gene expression profiling of JAK2V617F-mutant HSCs revealed a loss of specific regulator genes, some of which were restored to normal levels in single TET2/JAK2 mutant HSCs. Of these, Bmi1 and, to a lesser extent, Pbx1 and Meis1 overexpression in JAK2-mutant HSCs could drive a disease phenotype and retain durable stem cell self-renewal in functional assays. Together, these single-cell approaches refine the molecules involved in clonal expansion of MPNs and have broad implications for deconstructing the molecular network of normal and malignant stem cells.
dc.description.sponsorshipMS is the recipient of a BBSRC Industrial CASE PhD Studentship, and CAO and JF are recipients of Wellcome Trust PhD Studentships. Work in the Kent lab is supported by a Bloodwise Bennett Fellowship (15008), a European Hematology Association Non-Clinical Advanced Research Fellowship, and an ERC Starting Grant (ERC-2016-STG–715371). Work in the Green Lab is supported by the Wellcome Trust, Bloodwise, Cancer Research UK, the Kay Kendall Leukaemia Fund, and the Leukemia and Lymphoma Society of America. Dr. Kent, Professor Göttgens, and Professor Green are all supported by a core support grant from the Wellcome Trust and MRC to the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute the National Institute for Health Research Cambridge Biomedical Research Centre, the Cambridge Experimental Cancer Medicine Centre.
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.31846
dc.identifier.eissn1528-0020
dc.identifier.issn0006-4971
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/284470
dc.languageeng
dc.language.isoeng
dc.publisherAmerican Society of Hematology
dc.publisher.urlhttp://dx.doi.org/10.1182/blood-2017-12-821066
dc.subjectAmino Acid Substitution
dc.subjectAnimals
dc.subjectCell Self Renewal
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectHematologic Neoplasms
dc.subjectHematopoietic Stem Cells
dc.subjectJanus Kinase 2
dc.subjectMice
dc.subjectMice, Transgenic
dc.subjectMutation, Missense
dc.subjectMyeloproliferative Disorders
dc.subjectNeoplasm Proteins
dc.subjectNeoplastic Stem Cells
dc.titleSingle-cell approaches identify the molecular network driving malignant hematopoietic stem cell self-renewal.
dc.typeArticle
dcterms.dateAccepted2018-07-03
prism.endingPage803
prism.issueIdentifier8
prism.publicationDate2018
prism.publicationNameBlood
prism.startingPage791
prism.volume132
pubs.funder-project-idLeukaemia & Lymphoma Research (12029)
pubs.funder-project-idCancer Research UK (21762)
pubs.funder-project-idWellcome Trust (097922/B/11/Z)
pubs.funder-project-idMedical Research Council (MC_PC_12009)
pubs.funder-project-idMedical Research Council (MR/M008975/1)
pubs.funder-project-idMedical Research Council (MR/S036113/1)
pubs.funder-project-idBloodwise (15008)
pubs.funder-project-idEuropean Research Council (715371)
rioxxterms.licenseref.startdate2018-08
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1182/blood-2017-12-821066

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