Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Sister chromatid cohesion defects are associated with chromosomal copy number heterogeneity in high hyperdiploid childhood acute lymphoblastic leukemia

Moura-Castro, Larissa H. LU orcid ; Peña-Martínez, Pablo LU ; Castor, Anders LU ; Galeev, Roman LU ; Larsson, Jonas LU ; Järås, Marcus LU ; Yang, Minjun LU and Paulsson, Kajsa LU (2021) In Genes Chromosomes and Cancer 60(6). p.410-417
Abstract

High hyperdiploid acute lymphoblastic leukemia (ALL) is one of the most common malignancies in children. The main driver event of this disease is a nonrandom aneuploidy consisting of gains of whole chromosomes but without overt evidence of chromosomal instability (CIN). Here, we investigated the frequency and severity of defective sister chromatid cohesion—a phenomenon related to CIN—in primary pediatric ALL. We found that a large proportion (86%) of hyperdiploid cases displayed aberrant cohesion, frequently severe, to compare with 49% of ETV6/RUNX1-positive ALL, which mostly displayed mild defects. In hyperdiploid ALL, cohesion defects were associated with increased chromosomal copy number heterogeneity, which could indicate increased... (More)

High hyperdiploid acute lymphoblastic leukemia (ALL) is one of the most common malignancies in children. The main driver event of this disease is a nonrandom aneuploidy consisting of gains of whole chromosomes but without overt evidence of chromosomal instability (CIN). Here, we investigated the frequency and severity of defective sister chromatid cohesion—a phenomenon related to CIN—in primary pediatric ALL. We found that a large proportion (86%) of hyperdiploid cases displayed aberrant cohesion, frequently severe, to compare with 49% of ETV6/RUNX1-positive ALL, which mostly displayed mild defects. In hyperdiploid ALL, cohesion defects were associated with increased chromosomal copy number heterogeneity, which could indicate increased CIN. Furthermore, cohesion defects correlated with RAD21 and NCAPG mRNA expression, suggesting a link to reduced cohesin and condensin levels in hyperdiploid ALL. Knockdown of RAD21 in an ALL cell line led to sister chromatid cohesion defects, aberrant mitoses, and increased heterogeneity in chromosomal copy numbers, similar to what was seen in primary hyperdiploid ALL. In summary, our study shows that aberrant sister chromatid cohesion is frequent but heterogeneous in pediatric high hyperdiploid ALL, ranging from mild to very severe defects, and possibly due to low cohesin or condensin levels. Cases with high levels of aberrant chromosome cohesion displayed increased chromosomal copy number heterogeneity, possibly indicative of increased CIN. These abnormalities may play a role in the clonal evolution of hyperdiploid pediatric ALL.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
acute lymphoblastic leukemia, aneuploidy, chromosomal instability, hyperdiploidy, sister chromatid cohesion
in
Genes Chromosomes and Cancer
volume
60
issue
6
pages
8 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:33368842
  • scopus:85099353067
ISSN
1045-2257
DOI
10.1002/gcc.22933
language
English
LU publication?
yes
id
81d15103-8276-49e1-b256-0b2301a8fb5f
date added to LUP
2021-01-27 10:19:18
date last changed
2024-06-13 06:20:00
@article{81d15103-8276-49e1-b256-0b2301a8fb5f,
  abstract     = {{<p>High hyperdiploid acute lymphoblastic leukemia (ALL) is one of the most common malignancies in children. The main driver event of this disease is a nonrandom aneuploidy consisting of gains of whole chromosomes but without overt evidence of chromosomal instability (CIN). Here, we investigated the frequency and severity of defective sister chromatid cohesion—a phenomenon related to CIN—in primary pediatric ALL. We found that a large proportion (86%) of hyperdiploid cases displayed aberrant cohesion, frequently severe, to compare with 49% of ETV6/RUNX1-positive ALL, which mostly displayed mild defects. In hyperdiploid ALL, cohesion defects were associated with increased chromosomal copy number heterogeneity, which could indicate increased CIN. Furthermore, cohesion defects correlated with RAD21 and NCAPG mRNA expression, suggesting a link to reduced cohesin and condensin levels in hyperdiploid ALL. Knockdown of RAD21 in an ALL cell line led to sister chromatid cohesion defects, aberrant mitoses, and increased heterogeneity in chromosomal copy numbers, similar to what was seen in primary hyperdiploid ALL. In summary, our study shows that aberrant sister chromatid cohesion is frequent but heterogeneous in pediatric high hyperdiploid ALL, ranging from mild to very severe defects, and possibly due to low cohesin or condensin levels. Cases with high levels of aberrant chromosome cohesion displayed increased chromosomal copy number heterogeneity, possibly indicative of increased CIN. These abnormalities may play a role in the clonal evolution of hyperdiploid pediatric ALL.</p>}},
  author       = {{Moura-Castro, Larissa H. and Peña-Martínez, Pablo and Castor, Anders and Galeev, Roman and Larsson, Jonas and Järås, Marcus and Yang, Minjun and Paulsson, Kajsa}},
  issn         = {{1045-2257}},
  keywords     = {{acute lymphoblastic leukemia; aneuploidy; chromosomal instability; hyperdiploidy; sister chromatid cohesion}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{6}},
  pages        = {{410--417}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Genes Chromosomes and Cancer}},
  title        = {{Sister chromatid cohesion defects are associated with chromosomal copy number heterogeneity in high hyperdiploid childhood acute lymphoblastic leukemia}},
  url          = {{http://dx.doi.org/10.1002/gcc.22933}},
  doi          = {{10.1002/gcc.22933}},
  volume       = {{60}},
  year         = {{2021}},
}