title: Analysis of ABL kinase domain mutations conferring resistance to tyrosine kinase inhibitors in chronic myeloid leukemia cases from India.
abstract: BACKGROUND
  The current study was undertaken to find out the frequency and distribution of ABL kinase domain (KD) mutations showing resistance to tyrosine kinase inhibitors (TKI) in CML patients from India.
  
  
  METHODS
  A total of 24 TKI resistant CML patients were screened for ABL KD mutation by semi-nested reverse transcription PCR and sequencing. The expression of BCR-ABL transcripts was quantified by Real Time Taqman assay.
  
  
  RESULTS
  Sixteen different point mutations were detected in 14 (58.3%) of 24 TKI resistant patients. Five out of the 16 mutations were located at the four hot spots of ABL kinase domain: one at the P-loop (Q252H), one at the imatinib binding site (T315I), two at the catalytic domain (M351, Y353F) and one at the active A loop (H396P). The three mutations, viz. M244V, T315I and A380V, were the most frequent mutations and accounted for 40.9% of all resistance associated mutations.
  
  
  CONCLUSIONS
  In the present study, the presence of ABL KD mutations was found to be a major cause of drug resistance. The T315I mutation was found to be resistant to second generation drugs such as dasatinib. The study reinforces the need for new therapeutic options which can target this mutation.
authors: Research and Development, Super Religare Laboratories, Mumbai, India.
authors: Sarita
authors: S
authors: Bagadi
authors: Tapan
authors: T
authors: Saikia
authors: Ayaskant
authors: A
authors: Pany
authors: Bibhu
authors: B
authors: Das
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D001665:Binding Sites; D001752:Blast Crisis / Q000188:drug therapy / Q000235:genetics; D020134:Catalytic Domain; D004273:DNA, Neoplasm / Q000187:drug effects; D000069439:Dasatinib; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D005787:Gene Frequency; D016313:Genes, abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004273:DNA, Neoplasm; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; C406060:abl-bcr fusion protein, human; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib