Abstract 752: Dynamic interaction between TAL1 oncoprotein and LSD1 regulates TAL1 function in leukemogenesis.

Abstract

Abstract TAL1/SCL is a hematopoietic specific member of the basic Helix-Loop-Helix (bHLH) family of transcription factors important for the development of all hematopoietic lineages and pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL). TAL1 is a phosphorylated protein and its activities are mediated by the corepressors and coactivators that associate with TAL1. However, the functional link between phosphorylation and the recruitment of co-regulators by TAL1 is currently unknown. Here we reported that Protein kinase A (PKA) mediated phosphorylation regulates TAL1 interaction with the lysine specific demethylase (LSD1) that removes methyl group from methylated Lys 4 on histone H3 tails. We expressed the TAL1 mutant that deleted the LSD1 interacting domain in Murine erythroleukemia cells (MEL) and showed that the deletion of the LSD1 interacting domain of TAL1 leads to a promotion of erythroid differentiation and H3K4 hypermethylation of the P4.2 promoter accompanied by decreased interaction with LSD1. TAL1 directly interacts with LSD1, and the interacting domain encompasses amino acids 142-185 proximal to the bHLH domain, which contains a serine 172 residue that becomes phosphorylated by PKA during the transcriptional activation of TAL1. Phosphorylation of serine 172 in TAL1 specifically destabilizes the TAL1-LSD1 interaction that leads to promoter H3K4 hypermethylation and activation of target genes that have been suppressed in normal and malignant hematopoiesis. Knockdown of TAL1 or LSD1 led to a derepression of the TAL1 targets pre-Tα and p21, accompanied by reduced recruitment of LSD1 and increased H3K4 methylation at their enhancer/promoter regions in T cell acute lymphoblast leukemia (T-ALL) Jurkat cells. Similarly, treatment of PKA activator forskolin resulted in derepression of target genes by reducing its interaction with LSD1 while PKA inhibitor H89 represses them by suppressing H3K4 methylation levels. Consistent with the dual roles of TAL1 in transcription, TAL1 associated LSD1 is decreased while recruitment of hSET1 is increased at the TAL1 targets during erythroid differentiation. This process is accompanied by a dramatic increase in H3K4 methylation. Thus, our results suggest that the dynamic regulation of TAL1 and its associated histone demethylase LSD1 by PKA mediated phosphorylation controls the transcription of the TAL1 target genes via modulating the promoter H3K4 methylation. Our data revealed a novel interplay between PKA phosphorylation and TAL1 mediated epigenetic regulation that regulates hematopoietic transcription and differentiation programs during hematopoiesis and leukemogenesis. Citation Format: Ying Li, Changwang Deng, Yi Qiu, suming huang. Dynamic interaction between TAL1 oncoprotein and LSD1 regulates TAL1 function in leukemogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 752. doi:10.1158/1538-7445.AM2013-752