Molecular basis of lymphoblastic leukaemia Investigation of the molecular basis of cancer is central to interpreting therapy responses and designing new therapies. Health © Thinkstock T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive haematologic cancer associated with a high white blood cell count. Treatment entails the administration of glucocorticoids to induce growth arrest and apoptosis in lymphoid progenitor cells. However, a significant percentage of patients present with drug resistance leading to disease relapse. Accumulating evidence suggests that a combination of factors such as primary oncogenic lesions responsible for T-cell transformation and secondary mutations selected during glucocorticoid therapy probably mediate drug resistance. In this context, the EU-funded (TIGRE) (Targeting glucocorticoid resistance in T-ALL: a systems biology approach) project worked to identify novel genes and pathways involved in T-cell transformation and glucocorticoid resistance in T-ALL. Initially, scientists investigated the role of TLX1 and TLX3 - two transcription factors activated by oncogenic chromosomal translocations - by analysing the gene expression profile of leukaemic cells. Results indicated that the malignant activation of TLX1 and TLX3 disrupts the mitotic checkpoint and induces aneuploidy at the earliest stages of leukemic transformation. Analysis of the transcriptional networks and the genetic regulatory programmes of these transcription factors identified RUNX1 as the major regulator. These findings also supported a tumour suppressor role for this transcription factor in the pathogenesis of T-ALL. This was reinforced by the association observed in T-ALL cases with Runx1 mutations having high risk of treatment failure and poor prognosis. Notch signalling promotes growth and proliferation of normal immature T cells and this pathway is deregulated in T-ALL. Significant efforts were devoted to deciphering the role of Notch signalling in glucocorticoid resistance. For this purpose, scientists characterised the genomic landscape of NOTCH1 direct target genes in T-ALL and identified a wide range of new genes involved in T-cell transformation. Finally, the discovery that ETS1 and RUNX1 also participate in the regulation of the NOTCH1 target genes opens up a new avenue for the therapeutic exploitation of ETS1 and RUNX1 inhibitors in the treatment of T-ALL. Keywords T-cell acute lymphoblastic leukaemia, drug resistance, glucocorticoid, Notch signalling, RUNX1
