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Hematologic β-Tubulin VI Isoform Exhibits Genetic Variability That Influences Paclitaxel Toxicity

2012; American Association for Cancer Research; Volume: 72; Issue: 18 Linguagem: Inglês

10.1158/0008-5472.can-11-2861

1538-7445

Luis J. Leandro‐García, Susanna Leskelä, Lucía Inglada‐Pérez, Iñigo Landa, Aguirre A. de Cubas, Agnieszka Maliszewska, Iñaki Comino‐Méndez, Rocío Letón, Álvaro Gómez-Graña, Raúl Torres, Juan Carlos Ramírez, Sara Álvarez, José Rivera, Constantino Martı́nez, Marı́a Luisa Lozano, Alberto Cascón, Mercedes Robledo, Cristina Rodríguez‐Antona,

Cancer Treatment and Pharmacology

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.