Hematologic β-tubulin VI isoform exhibits genetic variability that influences paclitaxel toxicity.
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.
Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain.
Luis J
LJ
Leandro-García
Susanna
S
Leskelä
Lucía
L
Inglada-Pérez
Iñigo
I
Landa
Aguirre A
AA
de Cubas
Agnieszka
A
Maliszewska
Iñaki
I
Comino-Méndez
Rocío
R
Letón
Álvaro
Á
Gómez-Graña
Raúl
R
Torres
Juan Carlos
JC
Ramírez
Sara
S
Álvarez
José
J
Rivera
Constantino
C
Martínez
María Luisa
ML
Lozano
Alberto
A
Cascón
Mercedes
M
Robledo
Cristina
C
Rodríguez-Antona
D000970:Antineoplastic Agents / Q000009:adverse effects; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008870:Microtubules / Q000187:drug effects*; D017239:Paclitaxel / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000235:genetics; D014404:Tubulin / Q000235:genetics* / Q000378:metabolism
D000970:Antineoplastic Agents; D020033:Protein Isoforms; D014404:Tubulin; D017239:Paclitaxel