2026-07-23T17:11:50Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/174992024-11-29T22:11:22Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Leandro-García, Luis J
author
Leskelä, Susanna
author
Inglada-Pérez, Lucía
author
Landa, Iñigo
author
de Cubas, Aguirre A
author
Maliszewska, Agnieszka
author
Comino-Méndez, Iñaki
author
Letón, Rocío
author
Gómez-Graña, Álvaro
author
Torres, Raúl
author
Ramírez, Juan Carlos
author
Álvarez, Sara
author
Rivera, José
author
Martínez, Constantino
author
Lozano, María Luisa
author
Cascón, Alberto
author
Robledo Batanero, Mercedes
author
Rodriguez Antona, Cristina
funder
Ministerio de Ciencia e Innovación (España)
2024-02-06T09:43:52Z
2024-02-06T09:43:52Z
2012-09-15
Cancer Res . 2012 ;72(18):4744-52.
10.1158/0008-5472.CAN-11-2861
1538-7445
Cancer research
22805305
http://hdl.handle.net/20.500.12105/17499
Cellular microtubules composed of α-β-tubulin heterodimers that are essential for cell shape, division, and intracellular transport are valid targets for anticancer therapy. However, not all the conserved but differentially expressed members of the β-tubulin gene superfamily have been investigated for their role in these settings. In this study, we examined roles for the hematologic isoform β-tubulin VI and functional genetic variants in the gene. β-tubulin VI was highly expressed in blood cells with a substantial interindividual variability (seven-fold variation in mRNA). We characterized DNA missense variations leading to Q43P, T274M, and R307H, and a rare nonsense variant, Y55X. Because variations in the hematologic target of microtubule-binding drugs might alter their myelosuppressive action, we tested their effect in cell lines stably expressing the different β-tubulin VI full-length variants, finding that the T274M change significantly decreased sensitivity to paclitaxel-induced tubulin polymerization. Furthermore, patients treated with paclitaxel and carrying β-tubulin VI T274M exhibited a significantly lower thrombocytopenia than wild-type homozygous patients (P = 0.031). Together, our findings define β-tubulin VI as a hematologic isotype with significant genetic variation in humans that may affect the myelosuppresive action of microtubule-binding drugs. A polymorphism found in a tubulin isoform expressed only in hemapoietic cells may contribute to the patient variation in myelosuppression that occurs after treatment with microtubule-binding drugs.
eng
Hematologic β-tubulin VI isoform exhibits genetic variability that influences paclitaxel toxicity.
journal article
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