Direct sequencing of the ABL Kinase domain to detect clinically relevant mutations in CML patients who exhibit poor response to imatinib therapy.
CML is a haematopoietic stem cell disease characterised by the 9:22 translocation, which fuses BCR gene with the ABL gene. STI 571 is a 2-phenylamino pyrimidine that targets the ATP binding site of the ABL kinase domain and is a very effective drug treatment for the majority of CML patients. However, a proportion of patients respond partially or acquire clinical resistance after achieving a response. One of the mechanisms for resistance is the acquisition of one or more point mutations’ in the ABL kinase domain region, the section that interacts and binds the STI molecule. Mutations have been demonstrated in the catalytic and activation domains but the mutations tend to cluster in the highly conserved P loop region. A particular mutation, the T315I, produces complete resistance to STI while some of the other mutations confer partial resistance and can be negated by an escalating dose regime. Patients with P-loop mutations tend to have a poor overall survival. Therefore it is necessary to discover whether a patients’ lack of response is due to a mutation and to identify any mutations present.
Synonyms or keywords:
TK domain, tyrosine kinase domain mutation, Imatinib resistance, CML, chronic myeloid leukaemia, BCR ABL, t(9:22) , STI, tyrosine kinase inhibitor, imatininb, ATP binding site, T315I, P Loop.