International journal of molecular sciences · 2022
Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma.
СтатьяНазвание и аннотация: Перевод в очереди
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Schedel Anne, Friedrich Ulrike Anne, Morcos Mina N F, Wagener Rabea, Mehtonen Juha, Watrin Titus, Saitta Claudia, Brozou Triantafyllia, Michler Pia, Walter Carolin, Försti Asta, Baksi Arka, Menzel Maria, Horak Peter, Paramasivam Nagarajan, Fazio Grazia, Autry Robert J, Fröhling Stefan, Suttorp Meinolf, Gertzen Christoph, Gohlke Holger, Bhatia Sanil, Wadt Karin, Schmiegelow Kjeld, Dugas Martin, Richter Daniela, Glimm Hanno, Heinäniemi Merja, Jessberger Rolf, Cazzaniga Gianni, Borkhardt Arndt, Hauer Julia, Auer Franziska
Аннотация
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.