Germline ERG haploinsufficiency defines a new syndrome with cytopenia and hematological malignancy predisposition

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dc.contributor.authorZerella, J.R.
dc.contributor.authorHoman, C.C.
dc.contributor.authorArts, P.
dc.contributor.authorLin, X.
dc.contributor.authorSpinelli, S.J.
dc.contributor.authorVenugopal, P.
dc.contributor.authorBabic, M.
dc.contributor.authorBrautigan, P.
dc.contributor.authorTruong, L.
dc.contributor.authorArriola-Martinez, L.A.
dc.contributor.authorMoore, S.
dc.contributor.authorHollins, R.
dc.contributor.authorParker, W.
dc.contributor.authorNguyen, H.
dc.contributor.authorKassahn, K.S.
dc.contributor.authorBranford, S.
dc.contributor.authorFeurstein, S.K.
dc.contributor.authorLarcher, L.
dc.contributor.authorSicre de Fontbrune, F.
dc.contributor.authorDemirdas, S.
dc.contributor.authoret al.
dc.date.issued2024
dc.description.abstractThe genomics era has facilitated discovery of new genes predisposing to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ERG as a novel autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor critical for definitive hematopoiesis, stem cell function and platelet maintenance. ERG colocalizes with other transcription factors including RUNX1 and GATA2 on promoters/enhancers of genes orchestrating hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 thrombocytopenic individuals from one family and 14 additional ERG variants in unrelated individuals with BMF/HM including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germline ERG variants included cytopenias (thrombocytopenia, neutropenia, pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense, 1 truncating) including 3 missense population variants were functionally characterized. Thirteen potentially pathogenic ETS domain missense variants displayed loss-of-function characteristics disrupting transcriptional transactivation, DNA-binding and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture, and to promote acute erythroleukemia when transplanted into mice, concordant with these variants being loss-of-function. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germline ERG variants has clinical implications for patient/family diagnosis, counselling, surveillance, and treatment strategies including selection of bone marrow donors or cell/gene therapy.
dc.description.statementofresponsibilityJiarna R. Zerella, Claire C. Homan, Peer Arts, Xuzhu Lin, Sam J. Spinelli, Parvathy Venugopal, Milena Babic, Peter J. Brautigan, Lynda Truong, Luis Arriola-Martinez, Sarah Moore, Rachel Hollins, Wendy T. Parker, Hung Nguyen, Karin S. Kassahn, Susan Branford, Simone Feurstein, Lise Larcher, Flore Sicre de Fontbrune, Serwet Demirdas, Sonja de Munnik, Hélene Antoine-Poirel, Benedicte Brichard, Sahar Mansour, Kristiana Gordon, ERG Variants Research Network, Marcin W. Wlodarski, Ashwin Koppayi, Sara Dobbins, Pim G. N. J. Mutsaers, Kim E. Nichols, Ninad Oak, Desiree DeMille, Rong Mao, Ali Crawford, Julie McCarrier, Donald Basel, Josue Flores-Daboub, Michael W. Drazer, Kerry Phillips, Nicola K. Poplawski, Graeme M. Birdsey, Daniela Pirri, Pia Ostergaard, Annet Simons, Lucy A. Godley, David M. Ross, Devendra K. Hiwase, Jean Soulier, Anna L. Brown, Catherine L. Carmichael, Hamish S. Scott, and Christopher N. Hahn
dc.identifier.citationBlood, 2024; 144(17):1765-1780
dc.identifier.doi10.1182/blood.2024024607
dc.identifier.issn0006-4971
dc.identifier.issn0006-4971
dc.identifier.orcidHoman, C.C. [0000-0003-2847-8586]
dc.identifier.orcidArts, P. [0000-0002-6742-6239]
dc.identifier.orcidVenugopal, P. [0000-0002-1057-2438]
dc.identifier.orcidKassahn, K.S. [0000-0002-1662-3355]
dc.identifier.orcidBranford, S. [0000-0002-1964-3626] [0000-0002-5095-7981]
dc.identifier.orcidRoss, D.M. [0000-0001-7171-2935]
dc.identifier.orcidHiwase, D.K. [0000-0002-6666-3056]
dc.identifier.orcidBrown, A.L. [0000-0002-9023-0138]
dc.identifier.orcidScott, H.S. [0000-0002-5813-631X]
dc.identifier.orcidHahn, C.N. [0000-0001-5105-2554]
dc.identifier.urihttps://hdl.handle.net/2440/144079
dc.language.isoen
dc.publisherAmerican Society of Hematology (ASH Publications)
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1024215
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1164601
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1023059
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1182318
dc.rights© 2024 by American Society of Hematology
dc.source.urihttp://dx.doi.org/10.1182/blood.2024024607
dc.subjectbone marrow failure (BMF); hematological malignancy (HM); ETS-related gene (ERG)
dc.subject.meshAnimals
dc.subject.meshHumans
dc.subject.meshMice
dc.subject.meshHematologic Neoplasms
dc.subject.meshThrombocytopenia
dc.subject.meshMyelodysplastic Syndromes
dc.subject.meshGenetic Predisposition to Disease
dc.subject.meshPedigree
dc.subject.meshGerm-Line Mutation
dc.subject.meshMutation, Missense
dc.subject.meshAdult
dc.subject.meshMiddle Aged
dc.subject.meshFemale
dc.subject.meshMale
dc.subject.meshCore Binding Factor Alpha 2 Subunit
dc.subject.meshHaploinsufficiency
dc.subject.meshTranscriptional Regulator ERG
dc.subject.meshCytopenia
dc.titleGermline ERG haploinsufficiency defines a new syndrome with cytopenia and hematological malignancy predisposition
dc.typeJournal article
pubs.publication-statusPublished

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