Toggle Main Menu Toggle Search

Open Access padlockePrints

Impaired condensin complex and Aurora B kinase underlie mitotic and chromosomal defects in hyperdiploid B-cell ALL

Lookup NU author(s): Dr Deepali Pal

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


Abstract

© 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.


Publication metadata

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


Altmetrics

Altmetrics provided by Altmetric


Share