Impaired condensin complex and Aurora B kinase underlie mitotic and chromosomal defects in hyperdiploid B-cell ALL
Por:
Molina, O, Vinyoles, M, Granada, I, Roca-Ho, H, Gutierrez-Aguera, F, Valledor, L, Lopez-Lopez, CM, Rodriguez-Gonzalez, P, Trincado, JL, Menendez, SPIT, Pal, D, Ballerini, P, den Boer, ML, Plensa, I, Perez-Iribarne, MM, Rodriguez-Perales, S, Calasanz, MJ, Ramirez-Orellana, M, Rodriguez, R, Camos, M, Calvo, M, Bueno, C and Menendez, P
Publicada:
16 jul 2020
Resumen:
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.
Filiaciones:
:
Josep Carreras Leukemia Res Inst, Barcelona, Spain
Univ Barcelona, Sch Med, Dept Biomed, Barcelona, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Canc CIBER ONC, Barcelona, Spain
:
Josep Carreras Leukemia Res Inst, Barcelona, Spain
Univ Barcelona, Sch Med, Dept Biomed, Barcelona, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Canc CIBER ONC, Barcelona, Spain
:
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Canc CIBER ONC, Barcelona, Spain
Germans Trias & Pujol Univ Hosp, Hematol Lab, Catalan Inst Oncol, Badalona, Spain
Roca-Ho, H:
Josep Carreras Leukemia Res Inst, Barcelona, Spain
Univ Barcelona, Sch Med, Dept Biomed, Barcelona, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Canc CIBER ONC, Barcelona, Spain
:
Josep Carreras Leukemia Res Inst, Barcelona, Spain
Univ Barcelona, Sch Med, Dept Biomed, Barcelona, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Canc CIBER ONC, Barcelona, Spain
Valledor, L:
Univ Oviedo, Dept Phys & Analyt Chem, Asturias, Spain
Lopez-Lopez, CM:
Univ Oviedo, Dept Phys & Analyt Chem, Asturias, Spain
Rodriguez-Gonzalez, P:
Univ Oviedo, Dept Phys & Analyt Chem, Asturias, Spain
:
Josep Carreras Leukemia Res Inst, Barcelona, Spain
Univ Barcelona, Sch Med, Dept Biomed, Barcelona, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Canc CIBER ONC, Barcelona, Spain
Menendez, SPIT:
Hosp Univ Cent Asturias, Inst Invest Sanitaria Principado Asturias ISPA, Oviedo, Spain
ISCIII, CIBER ONC, Madrid, Spain
Pal, D:
Newcastle Univ, Northern Inst Canc Res, Wolfson Childhood Canc Res Ctr, Newcastle Upon Tyne, Tyne & Wear, England
Northumbria Univ, Dept Appl Sci, Newcastle Upon Tyne, Tyne & Wear, England
Ballerini, P:
A Trousseau Hosp, Pediat Hematol, Paris, France
den Boer, ML:
Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands
Plensa, I:
Inst Recerca Hosp St Joan de Deu, Hematol Lab, Barcelona, Spain
Perez-Iribarne, MM:
Inst Recerca Hosp St Joan de Deu, Hematol Lab, Barcelona, Spain
Rodriguez-Perales, S:
Ctr Nacl Invest Oncol, Mol Cytogenet Grp, Madrid, Spain
Calasanz, MJ:
Univ Navarra, CIMA Lab Diagnost, Pamplona, Spain
Ramirez-Orellana, M:
Hosp Nino Jesus, Hematol Diagnost Lab, Madrid, Spain
Rodriguez, R:
Hosp Univ Cent Asturias, Inst Invest Sanitaria Principado Asturias ISPA, Oviedo, Spain
ISCIII, CIBER ONC, Madrid, Spain
Camos, M:
Inst Recerca Hosp St Joan de Deu, Hematol Lab, Barcelona, Spain
Inst Recerca Hosp St Joan de Deu, Dev Tumors Biol Grp, Leukemia & Other Pediat Hemopathies, Barcelona, Spain
ISCIII, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Barcelona, Spain
Calvo, M:
Univ Barcelona CCiTUB, Sci Ctr, Campus Clin, Barcelona, Spain
Univ Barcelona CCiTUB, Technol Ctr, Campus Clin, Barcelona, Spain
:
Josep Carreras Leukemia Res Inst, Barcelona, Spain
Univ Barcelona, Sch Med, Dept Biomed, Barcelona, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Canc CIBER ONC, Barcelona, Spain
:
Josep Carreras Leukemia Res Inst, Barcelona, Spain
Univ Barcelona, Sch Med, Dept Biomed, Barcelona, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Canc CIBER ONC, Barcelona, Spain
Inst Catalana Recerca & Estudis Avancats ICREA, Barcelona, Spain
Green Accepted, Green Published, Bronze
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