TAL1 Interferes with the Regulatory Function of the T-Cell Regulator BCL11B in T-ALL
Experimental Hematology(2018)
Abstract
The transcription factor TAL1 is a master regulator of hematopoiesis where it is essential for hematopoietic stem cells specification, self-renewal and differentiation to the erythroid and megakaryocyte lineages. In contrast, TAL1 is silenced early in T-cell progenitors and when aberrantly expressed, it induces T-cell acute lymphoblastic leukemia (T-ALL). It has been previously shown that the leukemic function of TAL1 entails inhibition of both T-cell differentiation and apoptosis. However, the molecular mechanism(s) of TAL1 induced leukemogenesis is not entirely clear. While TAL1 has been shown to directly regulate the expression of genes that control proliferation, apoptosis and differentiation, other non-mutually exclusive models have been proposed, including TAL1-mediated interference with critical T-cell regulators (e.g. E proteins). Through a proteomic screen for TAL1-interacting proteins in T-ALL we identified the transcription factor BCL11B, a major T-cell regulator, as a new interacting partner of TAL1.We hypothesized that the oncogenic function of TAL1 might be mediated, at least in part, through interference with the T cell regulatory function of BCL11B. Using a combination of Chromatin immunoprecipitation (ChIP) and TAL1 and BCL11B knockdowns followed by deep sequencing (ChIPseq and RNAseq) we demonstrate that TAL1 targets to disrupt the T-cell regulatory function of BCL11B. Indeed 60% of BCL11B genomic sites were also targeted by TAL1and the two proteins work together to directly block T cell differentiation and function, and apoptosis, while activating cell cycle. Phenotypic analyses ex vivo and in vivo validate the model that TAL1 subverts the function of the T-cell regulator BCL11B to maintain leukemic cell proliferation, while unexpectedly utilizing BCL11B for T-cell differentiation arrest. In conclusion our results show that in T-ALL, TAL1 deregulates the function of a transcription factor that is essential for the commitment of hematopoietic progenitors to the T-cell lineage, highlighting an important contribution of the transcriptional interference model in the overall mechanism of TAL1-mediated leukemogenesis.
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Key words
regulatory function,t-cell,t-all
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