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

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 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.

Clonal origin and development of high hyperdiploidy in childhood acute lymphoblastic leukaemia

“…To investigate whether the observed differences in heterogeneity were due to mutations in genes affecting genomic stability, we screened bulk WGS data, but no such correlation was seen (Supplementary Table 1 ). We further investigated whether increased heterogeneity correlated with the presence of sister chromatid cohesion defects in metaphase chromosomes, which we have recently reported to be associated with increased chromosomal heterogeneity in HeH ALL 14 . Indeed, #2, which had the second highest heterogeneity score, had a very high frequency of cohesion defects in metaphase cells (85%; Table 1 ).…”

Somatic Sex: On the Origin of Neoplasms With Chromosome Counts in Uneven Ploidy Ranges

“…With regard to the potential contribution of condensin complex and spindle assembly checkpoint impairments, Molina et al found that inhibition of the Aurora B kinase and the spindle assembly checkpoint produced substantial chromosomal instability in healthy CD34-positive hematopoietic cells, the outcome of which were indeed aneuploid cells with chromosomes that displayed ALL-typical structural and condensation defects (Molina et al, 2020). In support of these findings, Moura-Castro et al (2020) also observed similar severe cohesion defects in a large proportion of hyperdiploid cases, especially in those with an increased copy number heterogeneity. Nevertheless, even if one concedes that these observations are highly relevant, it still remains unclear what actually would trigger these disturbances in the first place.…”

Fully exploiting SNP arrays: a systematic review on the tools to extract underlying genomic structure

“…Studies on mosaicism detection in cancer mainly used BAFSegmentation, TAPS, PICNIC, GISTIC and CNAG relating acute myeloid leukemia [ 234 ], hyperdiploid childhood acute lymphoblastic leukemia [ 235 ], ossification of fibromyxoid tumors [ 236 ], gastric adenocarcinoma [ 237 ], hepatoblastoma [ 238 ], lymphoblastic leukemia [ 239 ] and non-Hodgkin B-cell lymphoma [ 240 ]. Also, mosaicism genotyping was performed with MoChA, MAD, BAFSegmentation and PICNICfor mastocytosis [ 241 ] and drug resistance.…”