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

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

doi:10.3390/ijms23095174

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

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 GertzenHolger 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

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English
Article number	5174
Journal	International Journal of Molecular Sciences
Volume	23
Issue number	9
DOIs	https://doi.org/10.3390/ijms23095174
State	Published - 1 May 2022
Externally published	Yes

Keywords

RAD21
acute lymphoblastic leukemia
cohesin complex
germline cancer predisposition
trio sequencing

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10.3390/ijms23095174

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Schedel, A., Friedrich, U. A., Morcos, M. N. F., Wagener, R., Mehtonen, J., Watrin, T., Saitta, C., Brozou, T., Michler, P., Walter, C., Försti, A., Baksi, A., Menzel, M., Horak, P., Paramasivam, N., Fazio, G., Autry, R. J., Fröhling, S., Suttorp, M., ... Auer, F. (2022). Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma. International Journal of Molecular Sciences, 23(9), Article 5174. https://doi.org/10.3390/ijms23095174

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title = "Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma",

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.",

keywords = "RAD21, acute lymphoblastic leukemia, cohesin complex, germline cancer predisposition, trio sequencing",

author = "Anne Schedel and Friedrich, {Ulrike Anne} and Morcos, {Mina N.F.} and Rabea Wagener and Juha Mehtonen and Titus Watrin and Claudia Saitta and Triantafyllia Brozou and Pia Michler and Carolin Walter and Asta F{\"o}rsti and Arka Baksi and Maria Menzel and Peter Horak and Nagarajan Paramasivam and Grazia Fazio and Autry, {Robert J.} and Stefan Fr{\"o}hling and Meinolf Suttorp and Christoph Gertzen and Holger Gohlke and Sanil Bhatia and Karin Wadt and Kjeld Schmiegelow and Martin Dugas and Daniela Richter and Hanno Glimm and Merja Hein{\"a}niemi and Rolf Jessberger and Gianni Cazzaniga and Arndt Borkhardt and Julia Hauer and Franziska Auer",

note = "Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2022",

month = may,

day = "1",

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Schedel, A, Friedrich, UA, Morcos, MNF, Wagener, R, Mehtonen, J, Watrin, T, Saitta, C, Brozou, T, Michler, P, Walter, C, Försti, A, Baksi, A, Menzel, M, Horak, P, Paramasivam, N, Fazio, G, Autry, RJ, Fröhling, S, Suttorp, M, Gertzen, C, Gohlke, H, Bhatia, S, Wadt, K, Schmiegelow, K, Dugas, M, Richter, D, Glimm, H, Heinäniemi, M, Jessberger, R, Cazzaniga, G, Borkhardt, A, Hauer, J & Auer, F 2022, 'Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma', International Journal of Molecular Sciences, vol. 23, no. 9, 5174. https://doi.org/10.3390/ijms23095174

TY - JOUR

T1 - Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma

AU - Schedel, Anne

AU - Friedrich, Ulrike Anne

AU - Morcos, Mina N.F.

AU - Wagener, Rabea

AU - Mehtonen, Juha

AU - Watrin, Titus

AU - Saitta, Claudia

AU - Brozou, Triantafyllia

AU - Michler, Pia

AU - Walter, Carolin

AU - Försti, Asta

AU - Baksi, Arka

AU - Menzel, Maria

AU - Horak, Peter

AU - Paramasivam, Nagarajan

AU - Fazio, Grazia

AU - Autry, Robert J.

AU - Fröhling, Stefan

AU - Suttorp, Meinolf

AU - Gertzen, Christoph

AU - Gohlke, Holger

AU - Bhatia, Sanil

AU - Wadt, Karin

AU - Schmiegelow, Kjeld

AU - Dugas, Martin

AU - Richter, Daniela

AU - Glimm, Hanno

AU - Heinäniemi, Merja

AU - Jessberger, Rolf

AU - Cazzaniga, Gianni

AU - Borkhardt, Arndt

AU - Hauer, Julia

AU - Auer, Franziska

PY - 2022/5/1

Y1 - 2022/5/1

N2 - 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.

AB - 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.

KW - RAD21

KW - acute lymphoblastic leukemia

KW - cohesin complex

KW - germline cancer predisposition

KW - trio sequencing

UR - http://www.scopus.com/inward/record.url?scp=85129433052&partnerID=8YFLogxK

U2 - 10.3390/ijms23095174

DO - 10.3390/ijms23095174

M3 - Article

AN - SCOPUS:85129433052

SN - 1661-6596

VL - 23

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

IS - 9

M1 - 5174

ER -

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

Abstract

Keywords

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