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Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma

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  • 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
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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.

Original languageEnglish
Article number5174
JournalInternational Journal of Molecular Sciences
Issue number9
Publication statusPublished - 5 May 2022

ID: 78010259