SCL/TAL1: a multifaceted regulator from blood development to disease

Abstract

SCL/TAL1 (stem cell leukemia/T-cell acute lymphoblastic leukemia [T-ALL] 1) is an essential transcription factor in normal and malignant hematopoiesis. It is required for specification of the blood program during development, adult hematopoietic stem cell survival and quiescence, and terminal maturation of select blood lineages. Following ectopic expression, SCL contributes to oncogenesis in T-ALL. Remarkably, SCL's activities are all mediated through nucleation of a core quaternary protein complex (SCL:E-protein:LMO1/2 [LIM domain only 1 or 2]:LDB1 [LIM domain-binding protein 1]) and dynamic recruitment of conserved combinatorial associations of additional regulators in a lineage- and stage-specific context. The finely tuned control of SCL's regulatory functions (lineage priming, activation, and repression of gene expression programs) provides insight into fundamental developmental and transcriptional mechanisms, and highlights mechanistic parallels between normal and oncogenic processes. Importantly, recent discoveries are paving the way to the development of innovative therapeutic opportunities in SCL T-ALL.

The pluripotency factor NANOG controls primitive hematopoiesis and directly regulates Tal1

“…We also show that Nanog directly represses the master hematopoietic regulator Tal1 (Porcher et al, 2017) through an upstream regulatory element located in an intron of the neighboring Stil gene. Interestingly, this site is occupied by NANOG only during the differentiation of ES cells to EpiLCs (Murakami et al, 2016).…”

An Integrated Framework for Genome Analysis Reveals Numerous Previously Unrecognizable Structural Variants in Leukemia Patients’ Samples

“…Since ZFPM2 is a transcriptional cofactor, we extracted from TCGA AML data those genes whose expression is correlated with that of ZFPM2 ( Figure 7C-D) and showed that those genes significantly overlapped with those bound by GATA2 and were enriched in proto-oncogenes and those associated with transcriptional misregulation in cancer ( Figure 7E). As shown in Figure 7F, GATA2 binds to the promoter of one such gene, TAL1, an erythroid differentiation factor (Porcher et al 2017), which suggests that TAL1 expression may be regulated by ZFPM2. Finally, a number of genes frequently altered in our cohort but not previously associated with Figure 7.…”

Transcriptional control of blood cell emergence

“…In line with this restricted temporal requirement, in vitro studies have demonstrated the critical role of SCL for the formation of haemangioblast [46] and HE [47]. As discussed elsewhere, SCL is also an important player in adult haematopoiesis and erythropoiesis [48].…”

“…Similar to ETV2, the expression of SCL is only temporally required for blood cell emergence as its conditional deletion in TIE2-expressing cells does not affect blood cell emergence [45]. As discussed elsewhere, SCL is also an important player in adult haematopoiesis and erythropoiesis [48]. As discussed elsewhere, SCL is also an important player in adult haematopoiesis and erythropoiesis [48].…”