Prediction of TKI (Tyrosine Kinase Inhibitor) resistance using ex vivo studies in CML (chronic myeloid leukemia) patients.

Summary of the proposed research project

·       CML develops as a result of chromosomal translocation of ABELSON 1 gene (ABL1, 171.74kb) on chromosome 9 to the Breakpoint Cluster Region gene (BCR, 137.83kb) on chromosome 22, resulting in shorter chromosome 22, known as Philadelphia (Ph) chromosome (t(9,22)(q34.1,q11.2)) (B Johansson. et al. 2002). The translocation process generates a BCR-ABL fusion gene giving rise to a BCR-ABL oncoprotein. RT-PCR based quantification of the BCR-ABL transcript, done serially, is the current standard of care to monitor response to therapy in CML patients. The benchmarks for various timepoints after starting TKI have been described and hold prognostic significance as well Current monitoring assays for CML depend on RNA-based  and DNA-based approaches, but have several limitations like sensitivity and different assays need to be used based on the transcript – Major, minor, micro etc. Thus an early predictor of loss of response is desirable.

·       Additionally patients not responding appropriately to TKIs, are tested for mutations in the ABL Kinase gene. Mutations like T315I occurs in the ATP binding domain and prevents the ATP from binding. The mutation is found in only 20% of the cases which are resistant and in most of the cases the mutations cannot be located. Thus an alternate strategy to look for mechanism of of resistance to TKIs is desirable.