Researchers have found an immune cell clue to the process of T-cell acute lymphoblastic leukaemia development.
Dr Takaomi Sanda of the National University of Singapore examined genetic mutations in T cells that cause them to multiply uncontrollably. They explain that the production of genes during T cell development is strictly controlled, with different genes being turned on and off at various stages of T-cell development.
The team looked in detail at the protein TAL1, a critical regulator of hematopoietic and vascular development. It is encoded by the TAL1 gene and mis-expressed in the majority of patients with T-cell acute lymphoblastic leukaemia.
Tests on zebrafish showed that TAL1 activates a molecular switch called a super-enhancer, triggering the activation of a cluster of genes called GIMAP.
In Leukemia the team write: 'The GIMAP genes are expressed in haematopoietic stem cells and mature T cells but are downregulated during the immature stage of thymocyte differentiation.'
The GIMAP enhancer is activated by TAL1 in human T-cell acute lymphoblastic leukaemia cells, they add. 'Overexpression of human GIMAP genes in immature thymocytes alone does not induce tumorigenesis but accelerates leukaemia development. Our results demonstrate that aberrant activation of the GIMAP enhancer contributes to T-cell leukaemogenesis.'
Dr Sanda says: 'Currently, most of the patients with T-cell acute lymphoblastic leukaemia are young children. While recent improvements in chemotherapy have significantly boosted cure rates for T-cell acute lymphoblastic leukaemia, the introduction of intensive chemotherapy causes both short- and long-term adverse effects.
'Moreover, there are only a limited number of new drugs with specific activity against malignant T-cells. Moving forward, we are looking into identifying potential therapeutic compounds that inhibits the activation of this super-enhancer. We hope to be able to translate it into meaningful therapies for patients afflicted by T-cell acute lymphoblastic leukaemia.'
Source: Liau, W. S. et al. Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia. Leukemia 28 December 2016; doi:10.1038/leu.2016.392
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