학술논문
Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma
Document Type
article
Author
Anne Schedel; Ulrike Anne Friedrich; Mina N. F. Morcos; Rabea Wagener; Juha Mehtonen; Titus Watrin; Claudia Saitta; Triantafyllia Brozou; Pia Michler; Carolin Walter; Asta Försti; Arka Baksi; Maria Menzel; Peter Horak; Nagarajan Paramasivam; Grazia Fazio; Robert J Autry; Stefan Fröhling; Meinolf Suttorp; Christoph Gertzen; Holger Gohlke; Sanil Bhatia; Karin Wadt; Kjeld Schmiegelow; Martin Dugas; Daniela Richter; Hanno Glimm; Merja Heinäniemi; Rolf Jessberger; Gianni Cazzaniga; Arndt Borkhardt; Julia Hauer; Franziska Auer
Source
International Journal of Molecular Sciences, Vol 23, Iss 9, p 5174 (2022)
Subject
Language
English
ISSN
1422-0067
1661-6596
1661-6596
Abstract
Somatic loss of function mutations in cohesin genes are frequently associated with various cancer types, while cohesin disruption in the germline causes cohesinopathies such as Cornelia-de-Lange syndrome (CdLS). Here, we present the discovery of a recurrent heterozygous RAD21 germline aberration at amino acid position 298 (p.P298S/A) identified in three children with lymphoblastic leukemia or lymphoma in a total dataset of 482 pediatric cancer patients. While RAD21 p.P298S/A did not disrupt the formation of the cohesin complex, it altered RAD21 gene expression, DNA damage response and primary patient fibroblasts showed increased G2/M arrest after irradiation and Mitomycin-C treatment. Subsequent single-cell RNA-sequencing analysis of healthy human bone marrow confirmed the upregulation of distinct cohesin gene patterns during hematopoiesis, highlighting the importance of RAD21 expression within proliferating B- and T-cells. Our clinical and functional data therefore suggest that RAD21 germline variants can predispose to childhood lymphoblastic leukemia or lymphoma without displaying a CdLS phenotype.