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Lookup NU author(s): Dr Deepali Pal
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© 2020 by The American Society of Hematology.B-cell acute lymphoblastic leukemia (ALL; B-ALL) is the most common pediatric cancer, and high hyperdiploidy (HyperD) identifies the most common subtype of pediatric B-ALL. Despite HyperD being an initiating oncogenic event affiliated with childhood B-ALL, the mitotic and chromosomal defects associated with HyperD B-ALL (HyperD-ALL) remain poorly characterized. Here, we have used 54 primary pediatric B-ALL samples to characterize the cellular-molecular mechanisms underlying the mitotic/chromosome defects predicated to be early pathogenic contributors in HyperD-ALL. We report that HyperD-ALL blasts are low proliferative and show a delay in early mitosis at prometaphase, associated with chromosome-alignment defects at the metaphase plate leading to robust chromosome-segregation defects and nonmodal karyotypes. Mechanistically, biochemical, functional, and mass-spectrometry assays revealed that condensin complex is impaired in HyperD-ALL cells, leading to chromosome hypocondensation, loss of centromere stiffness, and mislocalization of the chromosome passenger complex proteins Aurora B kinase (AURKB) and Survivin in early mitosis. HyperD-ALL cells show chromatid cohesion defects and an impaired spindle assembly checkpoint (SAC), thus undergoing mitotic slippage due to defective AURKB and impaired SAC activity, downstream of condensin complex defects. Chromosome structure/condensation defects and hyperdiploidy were reproduced in healthy CD34+ stem/progenitor cells upon inhibition of AURKB and/or SAC. Collectively, hyperdiploid B-ALL is associated with a defective condensin complex, AURKB, and SAC.
Author(s): Molina O, Vinyoles M, Granada I, Roca-Ho H, Gutierrez-Aguera F, Valledor L, Lopez-Lopez CM, Rodriguez-Gonzalez P, Trincado JL, Menendez ST, Pal D, Ballerini P, den Boer ML, Plensa I, Mar Perez-Iribarne M, Rodriguez-Perales S, Calasanz MJ, Ramirez-Orellana M, Rodriguez R, Camos M, Calvo M, Bueno C, Menendez P
Publication type: Article
Publication status: Published
Journal: Blood
Year: 2020
Volume: 136
Issue: 3
Pages: 313-327
Online publication date: 16/07/2020
Acceptance date: 27/03/2020
ISSN (print): 0006-4971
ISSN (electronic): 1528-0020
Publisher: American Society of Hematology
URL: https://doi.org/10.1182/blood.2019002538
DOI: 10.1182/blood.2019002538
PubMed id: 32321174
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