New molecular targets in acute lymphoblastic leukaemia treatment
T-ALL is an aggressive malignancy characterised by the accumulation of undifferentiated thymocytes that have acquired multiple genomic mutations in transcriptional and signalling pathways. The EU-funded MOLTALL (Molecularly targeted therapy for T cell acute lymphoblastic leukemia) project aimed to expand the molecular characterisation of T-ALL-associated oncogenes that specifically provide proliferation and survival advantages to cancer. To obtain a comprehensive picture of the development of T-ALL from primary disease to relapse, researchers carried out an integrated genomic analysis of patients at the time of primary diagnosis, during remission and at relapse. As the next step they have generated cell-based and mouse models to verify the tumorigenic properties of newly identified genes. The results of the project identified new tumour suppressor genes in T-ALL that are involved in translational control such as the tyrosine phosphatases PTPN2 and PTPRC as well as the ribosomal protein RPL5, and CNOT3. In addition, a member of tyrosine kinase family JAK3, interleukin receptor 7 (IL7R), and ribosomal protein RPL10 were identified as the new oncogenes in T-ALL. Researchers also characterised the spectrum of mutations present in T-ALL using new sequencing technologies. Taken together, these data revealed the presence of new tumour suppressors and oncogenic pathways that are implicated in the development and progression of T-ALL. Most importantly, they indicate that JAK kinase inhibitors (targeting JAK3 or IL7R mutants) may represent promising new drugs that should be further investigated for the treatment of T-ALL.
Keywords
Acute lymphoblastic leukaemia, MOLTALL, tumour suppressor gene, JAK3, oncogene
