Leandro-García, Luis JLeskelä, SusannaInglada-Pérez, LucíaLanda, Iñigode Cubas, Aguirre AMaliszewska, AgnieszkaComino-Méndez, IñakiLetón, RocíoGómez-Graña, ÁlvaroTorres, RaúlRamírez, Juan CarlosÁlvarez, SaraRivera, JoséMartínez, ConstantinoLozano, María LuisaCascón, AlbertoRobledo Batanero, MercedesRodriguez Antona, Cristina2024-02-062024-02-062012-09-15Cancer Res . 2012 ;72(18):4744-52.http://hdl.handle.net/20.500.12105/17499Cellular 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.engAMhttp://creativecommons.org/licenses/by-nc-nd/4.0/Antineoplastic AgentsGenetic Predisposition to DiseaseGenotypeHumansMicrotubulesPaclitaxelPolymorphism, Single NucleotideProtein IsoformsReverse Transcriptase Polymerase Chain ReactionThrombocytopeniaTubulinAttribution-NonCommercial-NoDerivatives 4.0 Internacional228053057218474410.1158/0008-5472.CAN-11-28611538-7445Cancer researchopen access