Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma
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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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 5174 |
| Tidsskrift | International Journal of Molecular Sciences |
| Vol/bind | 23 |
| Udgave nummer | 9 |
| ISSN | 1661-6596 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
J.H. is supported by ERC Stg 85222 ?PreventALL?, ERA Per Med.JTC 2018 ?GEPARD?, Deutsche Krebshilfe (DKH) Excellenz F?rderprorgamm 70114539 and Sonnenstrahl e.V. A.S. is supported by Deutsche Jos? Carreras Leuk?mie?Stiftung e.V. together with Gesellschaft f?r Paediatrische Onkologie und Haematologie e.V. G.C. is supported by the Italian Association for Cancer Research (AIRC), grant IG2018 n.21999; C.S., G.F. and G.C. are partly supported by the Monza parents committee ?Comitato Maria Letizia Verga?. M.H. and J.M. is supported by ERA Per Med.JTC 2018 ?GEPARD?. R.J. is supported by the Deutsche Forschungsgemeinschaft (DFG, JE150/31?1). R.W. acknowledges the financial support of the Forschungskommission (2020?28) Heinrich Heine University Duesseldorf. This article/publication is based upon work from COST Action LEukaemia GENe Discovery by data sharing, mining and collaboration (CA16223), supported by COST (European Cooperation in Science and Technology; www.cost.eu)The authors would like to thank all members of our groups for useful discussions and for their critical reading of the manuscript. Particular thanks goes to Helena Jambor, Glen Pearce, Dalileh Nabi, Evelin Schr?ck, Arne Jahn, Silke Furlan, Carolin Melzig and Rajanya Ghosh.
Funding Information:
Funding: J.H. is supported by ERC Stg 85222 “PreventALL”, ERA Per Med.JTC 2018 “GEPARD”, Deutsche Krebshilfe (DKH) Excellenz Förderprorgamm 70114539 and Sonnenstrahl e.V. A.S. is sup‐ ported by Deutsche José Carreras Leukämie‐Stiftung e.V. together with Gesellschaft für Paedi‐ atrische Onkologie und Haematologie e.V. G.C. is supported by the Italian Association for Cancer Research (AIRC), grant IG2018 n.21999; C.S., G.F. and G.C. are partly supported by the Monza par‐ ents committee ‘Comitato Maria Letizia Verga’. M.H. and J.M. is supported by ERA Per Med.JTC 2018 “GEPARD”. R.J. is supported by the Deutsche Forschungsgemeinschaft (DFG, JE150/31‐1). R.W. acknowledges the financial support of the Forschungskommission (2020‐28) Heinrich Heine University Duesseldorf. This article/publication is based upon work from COST Action LEukaemia GENe Discovery by data sharing, mining and collaboration (CA16223), supported by COST (Euro‐ pean Cooperation in Science and Technology; www.cost.eu)
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
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