title: Evolution of BCR/ABL gene mutation in CML is time dependent and dependent on the pressure exerted by tyrosine kinase inhibitor.
abstract: BACKGROUND
  Mutations in the ABL kinase domain and SH3-SH2 domain of the BCR/ABL gene and amplification of the Philadelphia chromosome are the two important BCR/ABL dependent mechanisms of imatinib resistance. Here, we intended to study the role played by TKI, imatinib, in selection of gene mutations and development of chromosomal abnormalities in Indian CML patients.
  
  
  METHODS
  Direct sequencing methodology was employed to detect mutations and conventional cytogenetics was done to identify Philadelphia duplication.
  
  
  RESULTS
  Among the different mechanisms of imatinib resistance, kinase domain mutations (39%) of the BCR/ABL gene were seen to be more prevalent, followed by mutations in the SH3-SH2 domain (4%) and then BCR/ABL amplification with the least frequency (1%). The median duration of occurrence of mutation was significantly shorter for patients with front line imatinib than those pre-treated with hydroxyurea. Patients with high Sokal score (p = 0.003) showed significantly higher incidence of mutations, as compared to patients with low/intermediate score. Impact of mutations on the clinical outcome in AP and BC was observed to be insignificant. Of the 94 imatinib resistant patients, only 1 patient exhibited duplication of Philadelphia chromosome, suggesting a less frequent occurrence of this abnormality in Indian CML patients.
  
  
  CONCLUSIONS
  Close monitoring at regular intervals and proper analysis of the disease resistance would facilitate early detection of resistance and thus aid in the selection of the most appropriate therapy.
authors: Department of Cytogenetics, National Institute of Immunohaematology, 13th Floor, New Multistoried Building, KEM Hospital Campus, Parel, Mumbai, 400012, India.
authors: Shantashri
authors: S
authors: Vaidya
authors: Department of Cytogenetics, National Institute of Immunohaematology, 13th Floor, New Multistoried Building, KEM Hospital Campus, Parel, Mumbai, 400012, India.
authors: Babu Rao
authors: BR
authors: Vundinti
authors: Department of Haematology, 10th Floor, New Multistoried Building, KEM Hospital, Parel, Mumbai, 400012, India.
authors: Chandrakala
authors: C
authors: Shanmukhaiah
authors: Institute of Haematology and Transfusion Medicine, Kolkata, West Bengal, 700073, India.
authors: Prantar
authors: P
authors: Chakrabarti
authors: Department of Cytogenetics, National Institute of Immunohaematology, 13th Floor, New Multistoried Building, KEM Hospital Campus, Parel, Mumbai, 400012, India.
authors: Kanjaksha
authors: K
authors: Ghosh
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D058674:Chromosome Duplication; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D009154:Mutation / Q000187:drug effects*; D059645:Mutation Rate; D009367:Neoplasm Staging; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D012641:Selection, Genetic / Q000187:drug effects*; D013997:Time Factors; D016896:Treatment Outcome; D018909:src Homology Domains
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl
references: Leukemia. 2008 Jun;22(6):1184-90
references: 18354488
references: Blood. 2007 Jan 1;109(1):58-60
references: 16973963
references: Cancer. 2009 Dec 1;115(23):5382-93
references: 19739234
references: Hematol Oncol. 2009 Dec;27(4):190-7
references: 19274615
references: J Clin Oncol. 2009 Dec 10;27(35):6041-51
references: 19884523
references: Blood. 2010 Oct 28;116(17):3278-85
references: 20519627
references: Ann Hematol. 2011 Jan;90(1):47-52
references: 20697894
references: Leuk Res. 2012 May;36(5):e110-2
references: 22387050
references: Mol Diagn Ther. 2012 Aug 1;16(4):251-9
references: 22873741
references: Blood. 2002 Aug 1;100(3):1014-8
references: 12130516
references: Cancer Cell. 2002 Aug;2(2):117-25
references: 12204532
references: Cell. 2003 Mar 21;112(6):831-43
references: 12654249
references: Blood. 2003 Jul 1;102(1):276-83
references: 12623848
references: Eur J Haematol. 2004 Jun;72(6):441-3
references: 15128424
references: Nature. 1981 Jan 29;289(5796):353-7
references: 6258076
references: Cancer Res. 1991 Jun 15;51(12):3075-9
references: 2039987
references: J Biol Chem. 1996 Aug 9;271(32):19585-91
references: 8702653
references: Haematologica. 2005 Jul;90(7):979-81
references: 15996937
references: Haematologica. 2006 Feb;91(2):235-9
references: 16461309
references: Clin Cancer Res. 2006 Dec 15;12(24):7374-9
references: 17189410
references: Blood. 2008 Jul 1;112(1):53-5
references: 18403620