Chromosomal translocations that produce fusion proteins are generally associated with the aetiology of haematologic malignancies. The search for specific tyrosine-kinase inhibitors of fusion proteins is an area of active research, following the success of imatinib-based therapy. We have described the transforming and tumourigenic activity of a new fusion protein, BCR-JAK2, obtained from a patient with acute lymphoblastic leukaemia (ALL).
This chimeric protein involves the fusion of the oligomerisation domain of BCR with the tyrosine-kinase domain of JAK2. JAK2 is a non-receptor tyrosine-kinase that mediates the signalling of different cytokine receptors and is crucial for normal haematopoiesis by recruiting effectors that act further down in proliferation and survival signalling. Our group was able to prove that cells expressing BCR-JAK2 developed tumours when injected subcutaneously into immunodeficient mice. In addition, using bone marrow precursors transplanted into a mouse transplant model, we demonstrated that BCR-JAK2 is the triggering force of a myeloproliferative syndrome with a fatal outcome.
These findings support the use of this model as a relevant preclinical tool to validate new therapeutic approaches with JAK2 inhibitors. This therapy justifies further research on the use alone or in combination with standard chemotherapy in the treatment of human cancers with high JAK2 activity. It has recently been published that 10% of high-risk paediatric acute lymphoblastic leukaemia cases present activating mutations and could be candidates for therapeutic interventions with JAK2 inhibitors.
ALL is the most common neoplasm in childhood and although most cases respond to treatment, 20% relapse, shortening survival. We therefore want to analyse high-risk ALL samples using next-generation sequencing technology (NGS) to determine the percentage of mutations in the JAK kinase family in the Spanish population. For this purpose, ALL samples will be obtained from hospitals throughout the country. The analysis of mutations will be correlated with clinical parameters to evaluate their prognostic value. Moreover, those mutations that may alter receptor function will be analysed in in vivo tests with mutated constructions to describe their effect on subsequent signalling pathways to the receptor.
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