title: Genetic basis for the increased expression of vacuolar H+ translocating ATPase genes upon imatinib treatment in human lymphoblastoid cells.
abstract: OBJECTIVE
  The role of v-ATPases in cancer biology is being increasingly recognized. Yeast studies indicate that the tyrosine kinase inhibitor imatinib may interact with the v-ATPase genes and alter the course of cancer progression. Data from humans in this regard are lacking.
  
  
  METHODS
  We constructed 55 lymphoblastoid cell lines from pedigreed, cancer-free human subjects and treated them with IC20 concentration of imatinib mesylate. Using these cell lines, we (i) estimated the heritability and differential expression of 19 genes encoding several subunits of the v-ATPase protein in response to imatinib treatment; (ii) estimated the genetic similarity among these genes; and (iii) conducted a high-density scan to find cis-regulating genetic variation associated with differential expression of these genes.
  
  
  RESULTS
  We found that the imatinib response of the genes encoding v-ATPase subunits is significantly heritable and can be clustered to identify novel drug targets in imatinib therapy. Further, five of these genes were significantly cis-regulated and together represented nearly half-log fold change in response to imatinib (p = 0.0107) that was homogenous (p = 0.2598).
  
  
  CONCLUSIONS
  Our results proffer support to the growing view that personalized regimens using proton pump inhibitors or v-ATPase inhibitors may improve outcomes of imatinib therapy in various cancers.
authors: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX 78227, USA. hkulkarn@txbiomedgenetics.org
authors: Hemant
authors: H
authors: Kulkarni
authors: Harald H H
authors: HH
authors: Göring
authors: Joanne E
authors: JE
authors: Curran
authors: Vincent
authors: V
authors: Diego
authors: Thomas D
authors: TD
authors: Dyer
authors: Shelley
authors: S
authors: Cole
authors: Ken R
authors: KR
authors: Walder
authors: Greg R
authors: GR
authors: Collier
authors: John
authors: J
authors: Blangero
authors: Melanie A
authors: MA
authors: Carless
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D000068877:Imatinib Mesylate; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D025262:Vacuolar Proton-Translocating ATPases