Germline ATG2B/GSKIP-containing 14q32 duplication predisposes to early clonal hematopoiesis leading to myeloid neoplasms.

Adolescent Adult Aged Autophagy-Related Proteins / genetics Biomarkers, Tumor / genetics Case-Control Studies Chromosomes, Human, Pair 14 / genetics Clonal Hematopoiesis DNA Copy Number Variations Disease Susceptibility Female Follow-Up Studies Gene Duplication Germ Cells Humans Leukemia, Myeloid, Acute / genetics Male Middle Aged Mutation Myelodysplastic Syndromes / genetics Myeloproliferative Disorders / genetics Prognosis Repressor Proteins / genetics Retrospective Studies Survival Rate Vesicular Transport Proteins / genetics Young Adult

Journal

Leukemia

ISSN: 1476-5551

Titre abrégé: Leukemia

Pays: England

ID NLM: 8704895

Informations de publication

Date de publication:
01 2022

Historique:

received: 01 03 2021

accepted: 02 06 2021

revised: 26 05 2021

pubmed: 27 6 2021

medline: 19 2 2022

entrez: 26 6 2021

Statut: ppublish

Résumé

The germline predisposition associated with the autosomal dominant inheritance of the 14q32 duplication implicating ATG2B/GSKIP genes is characterized by a wide clinical spectrum of myeloid neoplasms. We analyzed 12 asymptomatic carriers and 52 patients aged 18-74 years from six families, by targeted sequencing of 41 genes commonly mutated in myeloid malignancies. We found that 75% of healthy carriers displayed early clonal hematopoiesis mainly driven by TET2 mutations. Molecular landscapes of patients revealed two distinct routes of clonal expansion and leukemogenesis. The first route is characterized by the clonal dominance of myeloproliferative neoplasms (MPN)-driver events associated with TET2 mutations in half of cases and mutations affecting splicing and/or the RAS pathway in one-third of cases, leading to the early development of MPN, mostly essential thrombocythemia, with a high risk of transformation (50% after 10 years). The second route is distinguished by the absence of MPN-driver mutations and leads to AML without prior MPN. These patients mostly harbored a genomic landscape specific to acute myeloid leukemia secondary to myelodysplastic syndrome. An unexpected result was the total absence of DNMT3A mutations in this cohort. Our results suggest that the germline duplication constitutively mimics hematopoiesis aging by favoring TET2 clonal hematopoiesis.

Identifiants

DOI: 10.1038/s41375-021-01319-w PMID: 34172895

pubmed: 34172895

doi: 10.1038/s41375-021-01319-w

pii: 10.1038/s41375-021-01319-w

doi:

Substances chimiques

ATG2B protein, human 0

Autophagy-Related Proteins 0

Biomarkers, Tumor 0

GSKIP protein, human 0

Repressor Proteins 0

Vesicular Transport Proteins 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

126-137

Informations de copyright

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