Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/17499
Title
Hematologic β-tubulin VI isoform exhibits genetic variability that influences paclitaxel toxicity.
Author(s)
Leandro-García, Luis J | Leskelä, Susanna | Inglada-Pérez, Lucía | Landa, Iñigo | de Cubas, Aguirre A | Maliszewska, Agnieszka | Comino-Méndez, Iñaki | Letón, Rocío | Gómez-Graña, Álvaro | Torres, Raúl | Ramírez, Juan Carlos | Álvarez, Sara | Rivera, José | Martínez, Constantino | Lozano, María Luisa | Cascón, Alberto | Robledo Batanero, Mercedes CNIO | Rodriguez Antona, Cristina CNIO
Date issued
2012-09-15
Citation
Cancer Res . 2012 ;72(18):4744-52.
Language
Inglés
Document type
journal article
Abstract
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.
MESH
Antineoplastic Agents | Genetic Predisposition to Disease | Genotype | Humans | Microtubules | Paclitaxel | Polymorphism, Single Nucleotide | Protein Isoforms | Reverse Transcriptase Polymerase Chain Reaction | Thrombocytopenia | Tubulin
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