University of Cambridge > > Cancer Research UK Cambridge Institute (CRUK CI) Seminars in Cancer > Origins and clonal evolution of childhood leukaemia

Origins and clonal evolution of childhood leukaemia

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If you have a question about this talk, please contact Neil Bennett.

Childhood acute lymphoblastic leukaemia is thought in many cases to initiate in utero. The factors that influence the formation of the initiating lesions are not well understood although the nature of these genetic aberrations is well documented and include in approximately a quarter of children the presence of the t12;21 chromosomal translocation that fuses the transcription factors Tel (ETV6) and Aml1 (RUNX1). The Tel-Aml1 fusion gene produces a pre-leukaemic clone but in and of itself is insufficient to produce frank leukaemic transformation. For this, additional mutations are required and it remains unclear what factors influence their acquisition. These additional mutations tend to arise in loci that are normally involved in cell fate control in the B lineage. Cell fate regulators act in a context dependent manner and thus understanding the nature of the target cell or cells in which the initiating and subsequent mutations arise is of importance.

To gain insight with these issues we have been exploring the target genes of TEL -AML1 and associated second hits as well as developing new foetal specific models in which to examine the biological impact of TEL -AML1.

Leukaemic clones appear to evolve in a branching manner such that at presentation the marrow is replete with multiple variegated subtypes proving a diverse substrate for selection in response to therapy. Beyond genetic heterogeneity, leukaemic cells exhibit epigenetic heterogeneity in respect of their immunophenotypes and functional properties including cell cycle status and niche residence.

Overall, our studies suggest that clonal selection in leukaemia results from the combined influence of genetic and epigenetic variations.

This talk is part of the Cancer Research UK Cambridge Institute (CRUK CI) Seminars in Cancer series.

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