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

Jiarna Rose Zerella¹, Claire C Homan¹, Peer Arts¹, Xuzhu Lin², Sam John Spinelli¹, Parvathy Venugopal¹, Milena Babic¹, Peter Brautigan¹, Lynda Truong², Luis Alberto Arriola-Martinez¹, Sarah Moore³, Rachel Hollins³, Wendy Parker¹, Hung Nguyen³, Karin S Kassahn⁴, Susan Branford¹, Simone K Feurstein⁵, Lise Larcher⁶, Flore Sicre de Fontbrune⁷, Serwet Demirdas⁸, Sonja de Munnik⁹, Hélène A Poirel¹⁰, Benedicte Brichard¹¹, Sahar Mansour¹², Kristiana Gordon¹², Erg Variants Research Network¹³, Marcin W Wlodarski¹⁴, Ashwin Lakshman Koppayi¹⁵, Sara Dobbins¹², Pim G N J Mutsaers¹⁶, Kim E Nichols¹⁷, Ninad Oak¹⁷, Desiree DeMille¹⁸, Rong Mao¹⁸, Ali Crawford¹⁹, Julie McCarrier²⁰, Donald Basel²⁰, Josue Flores-Daboub²¹, Michael W Drazer²², Kerry Phillips²³, Nicola Poplawski²³, Graeme M Birdsey²⁴, Daniela Pirri²⁴, Pia Ostergaard¹², Annet Simons⁹, Lucy A Godley¹⁵, David M Ross¹, Devendra K Hiwase⁴, Jean Soulier⁶, Anna L Brown¹, Catherine L Carmichael², Hamish S Scott¹, Christopher N Hahn¹

Affiliations

¹ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia., Australia.
² Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia., Australia.
³ Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia., Australia.
⁴ Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia., Australia.
⁵ Department of Internal Medicine, Section of Hematology, Oncology & Rheumatology, University Hospital Heidelberg, Heidelberg, Germany., Germany.
⁶ Université Paris Cité, Inserm and Hôpital Saint-Louis, APHP, Paris, France., France.
⁷ Service d'hématologie-greffe, Hôpital Saint-Louis, Université Paris Cité, Paris, France., France.
⁸ Department of Clinical Genetics Erasmus Medical Center Rotterdam The Netherlands., Netherlands.
⁹ Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands., Netherlands.
¹⁰ Sciensano, Rue Juliette Wytsman 14, 1050 Brussels, Belgium., Belgium.
¹¹ Department of Pediatric hematology and oncology, Cliniques universitaires Saint-Luc, Brussels, Belgium., Belgium.
¹² Cardiovascular and Genomics Research Institute, St George's University of London, London, United Kingdom., United Kingdom.
¹³ N/A, N/A, Australia.
¹⁴ Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Germany.
¹⁵ Robert H. Lurie Comprehensive Cancer Center and Northwestern University., United States.
¹⁶ Department of Hematology, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands., Netherlands.
¹⁷ Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., United States.
¹⁸ ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT, USA., United States.
¹⁹ Illumina, Inc., San Diego, CA, USA., United States.
²⁰ Department of Pediatrics, Medical College of Wisconsin, Milwaukee WI, USA., United States.
²¹ Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA., United States.
²² Section of Hematology/Oncology, Department of Medicine, The University of Chicago, IL, USA., United States.
²³ Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia., Australia.
²⁴ National Heart and Lung Institute, Imperial College London, London, United Kingdom., United Kingdom.

PMID: 38991192
DOI: 10.1182/blood.2024024607

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

Jiarna Rose Zerella et al. Blood. 2024.

. 2024 Jul 11:blood.2024024607.

doi: 10.1182/blood.2024024607. Online ahead of print.

Authors

Affiliations

¹ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia., Australia.
² Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia., Australia.
³ Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia., Australia.
⁴ Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia., Australia.
⁵ Department of Internal Medicine, Section of Hematology, Oncology & Rheumatology, University Hospital Heidelberg, Heidelberg, Germany., Germany.
⁶ Université Paris Cité, Inserm and Hôpital Saint-Louis, APHP, Paris, France., France.
⁷ Service d'hématologie-greffe, Hôpital Saint-Louis, Université Paris Cité, Paris, France., France.
⁸ Department of Clinical Genetics Erasmus Medical Center Rotterdam The Netherlands., Netherlands.
⁹ Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands., Netherlands.
¹⁰ Sciensano, Rue Juliette Wytsman 14, 1050 Brussels, Belgium., Belgium.
¹¹ Department of Pediatric hematology and oncology, Cliniques universitaires Saint-Luc, Brussels, Belgium., Belgium.
¹² Cardiovascular and Genomics Research Institute, St George's University of London, London, United Kingdom., United Kingdom.
¹³ N/A, N/A, Australia.
¹⁴ Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Germany.
¹⁵ Robert H. Lurie Comprehensive Cancer Center and Northwestern University., United States.
¹⁶ Department of Hematology, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands., Netherlands.
¹⁷ Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., United States.
¹⁸ ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT, USA., United States.
¹⁹ Illumina, Inc., San Diego, CA, USA., United States.
²⁰ Department of Pediatrics, Medical College of Wisconsin, Milwaukee WI, USA., United States.
²¹ Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA., United States.
²² Section of Hematology/Oncology, Department of Medicine, The University of Chicago, IL, USA., United States.
²³ Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia., Australia.
²⁴ National Heart and Lung Institute, Imperial College London, London, United Kingdom., United Kingdom.

PMID: 38991192
DOI: 10.1182/blood.2024024607

Abstract

The 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.

PubMed Disclaimer

LinkOut - more resources

Full Text Sources
- Elsevier Science
- Silverchair Information Systems

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Similar articles

LinkOut - more resources

Full Text Sources

Abstract

Similar articles

Related information

LinkOut - more resources

Full Text Sources