Impaired Condensin Complex and Aurora B kinase underlie mitotic and chromosomal defects in hyperdiploid B-cell ALL

Oscar Molina, Meritxell Vinyoles, Isabel Granada, Heleia Roca-Ho, Francisco Gutierrez-Agüera, Luis Valledor, Carlos Manuel López-López, Pablo Rodríguez-González, Juan Luis Trincado, Sofía Tirados-Menéndez, Deepali Pal, Paola Ballerini, Monique L Den Boer, Isabel Plensa, Maria Del Mar Perez-Iribarne, Sandra Rodriguez-Perales, Maria Jose Calasanz, Manuel Ramírez, Rene Rodríguez, Mireia CamosMaria Calvo, Clara Bueno, Pablo Menendez

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3 Citations (Scopus)
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Abstract

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.

Original languageEnglish
Pages (from-to)313-327
Number of pages15
JournalBlood
Volume136
Issue number3
Early online date22 Apr 2020
DOIs
Publication statusPublished - 16 Jul 2020

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