-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

LBA-6 ERG Is a New Predisposition Gene for Bone Marrow Failure and Hematological Malignancy

Program: General Sessions
Session: Late-Breaking Abstracts Session
Hematology Disease Topics & Pathways:
Bleeding and Clotting, Acute Myeloid Malignancies, AML, Bone Marrow Failure Syndromes, Inherited Marrow Failure Syndromes, Genetic Disorders, Diseases, thrombocytopenias, Myeloid Malignancies
Tuesday, December 12, 2023, 9:00 AM-10:30 AM

Hamish S Scott, PhD, BSc1,2,3,4, Jiarna Zerella, BSc5*, Claire Homan6*, Peer Arts, BSc, PhD5*, Steve Lin7*, Sam J Spinelli8*, Milena Babic9*, Peter J Brautigan10*, Lynda Truong7*, Luis Arriola-Martinez11*, Parvathy Venugopal, PhD, MSc, BSc11*, Simone K Feurstein, MD12*, Lise Larcher13*, Flore Sicre De Fontbrune14*, Serwet Demirdas15*, Sonja De Munnik16*, Hélène Poirel17*, Benedicte Brichard18*, Sara Dobbins19*, Pim Mutsaers, MD20*, Desiree S DeMille21*, Josue Flores-Daboub22*, Michael W Drazer, MD, PhD23, Alison Crawford24*, Julie McCarrier25*, Donald G Basel25*, Kerry Phillips26*, Nicola K Poplawski, MD, FRACP26*, Graeme Birdsey27*, Daniela Pirri28*, Pia Ostergaard19*, Annet Simons29*, Lucy Godley, MD, PhD30, David M. Ross, MBBS, PhD, FRACP, FRCPA31,32,33*, Devendra Hiwase, MD, MBBS, PhD, FRACP, FRCPA34,35,36, Jean Soulier, MD37, Anna Brown, PhD, BSc2,4*, Catherine Carmichael, PhD38* and Christopher N. Hahn, PhD4,39,40*

1Genetics and Molecular Pathology, SA Pathology, St Peters, SA, Australia
2Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia
3University of Adelaide, Adelaide Medical School, Adelaide, SA, AUS
4Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia
5Centre For Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia
6Centre For Cancer Biology, SA Pathology and University of South Australia, Adelaide, AUS
7Centre for Cancer Research, The Hudson Institute of Medical Research,, Clayton, Australia
8Centre for Cancer Biology, Adelaide, Australia
9Centre For Cancer Biology (SA Pathology), Adelaide, SA, AUS
10SA Pathology, Adelaide, SA, AUS
11Centre for Cancer Biology, Adelaide, AUS
12University Hospital Heidelberg, Heidelberg, Germany
13Hopital Saint-Louis and University De Paris, Paris, FRA
14Hôpital Saint-Louis, Université Paris Cité, Paris, France
15Erasmus Medical Center, Rotterdam, Netherlands
16Radboud University Medical Center, Nijmegen, Netherlands
17Sciensano, Brussels, Belgium
18Cliniques universitaires st-Luc, Brussels, Belgium
19St George's University of London, London, United Kingdom
20Erasmus University Medical Centre, Rotterdam, Netherlands
21ARUP Institute for Clinical and Experimental Pathology, Salt Lake City
22University of Utah School of Medicine, Salt Lake City
23The University of Chicago, Chicago, IL
24Illumina, Inc., San Diego
25Medical College of Wisconsin and Children's Wisconsin, Milwaukee
26Royal Adelaide Hospital, Adelaide, Australia
27Imperial College London, London, GBR
28Imperial College London, London, United Kingdom
29Radboud University Medical Center, Nijmegen, NLD
30Northwestern University, Chicago, IL
31SA Pathology and South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia
32Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
33Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia
34Haematology, Central Adelaide Local Health Network (CALHN), Adelaide, SA, Australia
35Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
36Department of Haematology, SA Pathology, Adelaide, Australia
37Hôpital Saint-Louis, Paris, France
38Hudson Institute of Medical Research, Melbourne, VIC, AUS
39Molecular Pathology Research Laboratory, Adelaide, SA, AUS
40University of South Australia, Adelaide, SA, Australia

There remain gaps in our knowledge of hereditary and sporadic causes of hematological malignancy (HM) and bone marrow failure (BMF) that prevent optimal diagnosis, disease surveillance and treatment. Here we report the discovery of ERG as a novel predisposition gene for BMF and HM. ERG is a known oncogene, typically via gene-fusions, leading to dysregulated ERG overexpression in blood and solid cancers. We identified a germline ERG ETS domain variant p.Y373C segregating with thrombocytopenia in a mother, who progressed to AML (27 yr) and then therapy-related MDS (35 yr), and in her 2 sons. All three showed copy neutral loss of heterozygosity of all or part of chromosome 21q, including the ERG locus, with the oldest son showing at least 2 somatic genetic rescue (SGR) events. The possibility of causal RUNX1 variants were ruled out, with the smallest somatic cnLOH event beginning within the RUNX1 gene, but not encompassing the RUNT domain where the majority of pathogenic missense variants are located. ERG, a highly constrained gene (LOEUF <0.33), is critical for definitive hematopoiesis, adult hematopoietic stem cell (HSC) function and platelet maintenance. An identical corresponding heterozygous germline variant (p.Y343C) in ERG’s closest gene by homology, FLI1, causes platelet-type bleeding disorder-21 (BDPLT21, OMIM #617443).

Through global collaborations, we have identified 15 heterozygous variants in the ERG gene, 13 of which are missense and 2 truncating variants, in 17 individuals with cytopenia and/or HM (mainly myeloid) or lymphedema (Table). Onset of hematological symptoms ranged from birth to 38 years for truncating and constrained ETS domain variants. Of these 15 variants, 12 have been confirmed germline including 2 de novo. Only 4 meiotic transmissions are observed. None of the missense variants in the highly conserved ETS domain of ERG which mediates DNA binding, protein-protein interactions and nuclear localization, are present in gnomAD. We have functionally characterized 19 ERG variants, 12 potentially pathogenic, 1 known mouse pathogenic variant and 3 population controls demonstrating that most ETS domain missense variants display loss-of-function (LOF) characteristics disrupting transcriptional transactivation (Figure), DNA-binding and/or nuclear localization in vitro. Robust preliminary data from ex vivo models of ERG overexpression in mouse fetal liver cells in tissue culture (cytokine-independence), a mouse transplant assay and previous germline mutant Erg mouse models are concordant with ETS domain missense variants being LOF compared to wildtype ERG and benign controls. Together, these data provide clinical, in vitro and ex vivo functional studies implicating LOF variants in hematological disease predisposition. LOF ERG mutations also occur in sporadic cases of HM.

Recently, as part of a Genomics England Research Consortium population study, 4 truncating ERG variants were described in 7 individuals across 4 families with 3 meiotic transmissions and a de novo case with primary lymphedema (1) and we add 2 novel missense variants here. One patient showed SGR across the ERG locus in blood. Blood phenotypes were not described. Our results demonstrate that germline ERG variants predispose to diverse cytopenia, BMF and HM in both children and adults. In our family mentioned above, the mother received an unrelated alloHSCT due to t-MDS while her 2 sons with cytopenias continue to be monitored. The natural history of this new syndrome will require careful identification of germline lesions with additional longitudinal studies in more patients and families needed. This ERG syndrome parallels GATA2 deficiency syndrome (HM and lymphedema) and RUNX1 Familial Platelet disorder-myeloid malignancy (thrombocytopenia and HM). Like the well-known disease genes GATA2 and RUNX1, ERG is also a member of the transcription factor heptad involved in HSC maintenance and differentiation. ERG adds to a growing list of genes whose unregulated expression contributes to HM and other cancers.

Identification of causal germline ERG variants like those outlined in this study, has direct clinical implications for patient and family management including diagnosis, counselling, surveillance and treatment strategies such as selection of bone marrow transplant donors and potential for targeted therapies including gene and cell therapy.

1. Greene D et al. Nat.Med. 29:679-688 2023

Disclosures: Scott: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sicre De Fontbrune: Alexion, AstraZeneca Rare Disease: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sobi: Honoraria, Research Funding; Samsung: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Mutsaers: AstraZeneca: Research Funding; GlaxoSmithKline: Consultancy. DeMille: ARUP Laboratories: Current Employment. Crawford: Illumina: Current Employment. Soulier: STRM.Bio: Membership on an entity's Board of Directors or advisory committees; Rocket Pharmaceuticals: Consultancy, Honoraria.

<< Previous Presentation | Next Presentation