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oai:repisalud.isciii.es:20.500.12105/174992024-11-29T22:11:22Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc 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 author 2012-09-15 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. 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 Hematologic β-tubulin VI isoform exhibits genetic variability that influences paclitaxel toxicity.