Gene Expression Profiles in CML Non-responders

Gene Expression Profiles in CML Non-responders

Chronic myeloid leukaemia (CML) is a haematological malignancy primarily driven by the fusion oncogene BCR-ABL1, resulting in a constitutively expressed tyrosine kinase. CML is treated very effectively by the tyrosine kinase inhibitors (TKIs) resulting in almost undetectable levels of disease. However, some patients show resistance to first line treatment, requiring second and third generation TKIs. Such resistance is due to the presence of tyrosine kinase domain (TKD) mutations, however TKDs do not appear to be present in all patients who do not respond to treatment. The aim of this project is to utilise gene expression arrays to identify transcriptomic profiles associated with resistance to TKIs in the absence of a demonstrable TKD mutation. The presence of such profiles may allow for a more targeted approach to treatment, if non-responders can be identified earlier in the disease management pathway. Being able to predict those that will not respond to first line treatment will allow for better stratification of patients.

The aim of this project is to use gene expression microarrays to detect expression profiles which may be associated with TKI resistance in order to better stratify CML patients and allow a more targeted approach to therapy. The project may also help elucidate the mechanism of resistance in those without a discernible TKD mutation. Ultimately it is hoped that this would lead to larger studies which could improve the clinical pathway for CML patients without TKD mutations. Some previous studies have studied the gene expression profile of CML patients demonstrating resistance to TKIs, using Affymetrix arrays. However, none of these appear to have specifically investigated non-responders with and without a TKD mutation.

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