The consequences of the aberrant expression of TAL1 and its isoforms in T cell acute lymphoblastic leukaemia

Abstract

Most of the T-ALL cases aberrantly express the bHLH transcription factor TAL1. To further understand the role of TAL1 in T-ALL, we examined TAL1 protein interactions, genome-wide distribution, and assessed their mediated regulation of cellular processes. We identified proteins interactions networks associated with TAL1 and its interacting partner HEB, in T-ALL cells, including major regulators of T cell development. Our characterisation of the genomic occupancy of TAL1 interacting partners identified DNA methylation as a modulator of TAL1 transcriptional complex. Furthermore, TAL1 has four isoforms with described structural and functional differences in haematopoietic cells. Although mouse models indicate that long and short isoforms contribute to leukaemia, differential functional characteristics of TAL1 isoforms have not been investigated. We constructed four FLAG-tagged TAL1 isoforms constructs. We used the constructs to stably overexpress different TAL1 isoforms in T-ALL cells and human CD34+ cells undergoing T cell differentiation In-vitro. Our study found a differential genomic distribution of TAL1 depending on isoform overexpression and consequent effects on differentiation markers. We demonstrated that TAL1 overexpression resulted in an increase in early T cell differentiation markers which was not isoform-specific. Finally, our work highlights molecular mechanisms of TAL1 role in T-cell acute lymphoblastic leukaemia at the isoform level.