The T-ALL related gene BCL11B regulates the initial stages of human T-cell differentiation

Abstract

The initial stages of T-cell differentiation are characterized by a progressive commitment to the T-cell lineage, a process that involves the loss of alternative (myelo-erythroid, NK, B) lineage potentials. Aberrant differentiation during these stages can result in T-cell acute lymphoblastic leukemia (T-ALL). However, the mechanisms regulating the initial stages of human T-cell differentiation are obscure. Through loss of function studies we showed BCL11B, a transcription factor recurrently mutated T-ALL, is essential for T-lineage commitment, particularly the repression of NK and myeloid potentials and the induction of T-lineage genes, during the initial stages of human T-cell differentiation. In gain of function studies, BCL11B inhibited growth of and induced a T-lineage transcriptional program in T-ALL cells. We found previously unknown differentiation stage-specific DNA binding of BCL11B at multiple T-lineage genes; target genes showed BCL11B dependent expression, suggesting a transcriptional activator role for BCL11B at these genes. Transcriptional analyses revealed differences in the regulatory actions of BCL11B between human and murine thymopoiesis. Our studies show BCL11B is a key regulator of the initial stages of human T-cell differentiation and delineate the BCL11B transcriptional program, enabling the dissection of the underpinnings of normal T-cell differentiation and providing a resource for understanding dysregulations in T-ALL.

Epigenomic translocation of H3K4me3 broad domains over oncogenes following hijacking of super-enhancers

“…To investigate the wider involvement of H3K4m3-BDs in T-ALL we considered the T-cell identity (Ha et al 2017) and tumour suppressor gene, BCL11B that is rearranged in T-ALL (Liu et al 2017). Since this gene is known to be regulated by an upstream super-enhancer element (Nagel et al 2007; L. Li et al 2013), we questioned whether the relocation of this region from chromosome 14 band q32 next to TLX3 on chromosome 5 band q35 would result in the appearance of an aberrant H3K4me3-BD over the coding region of the gene.…”

Distinct Notch1 and BCL11B requirements mediate human γδ/αβ T cell development

“…Higher BCL11B levels are required for human TCRab compared to the levels for TCRcd T cell development To validate whether differential BCL11B expression levels have a functional impact on human T cell development, we performed shRNA-mediated knockdown experiments in human CD34 + thymocytes that were subsequently cultured in ATOs [45]. We selected two shRNAs that induced around 50% reduction in BCL11B protein levels ( Fig 8A) [47] which correlated with the observed difference between developing cdand ab-lineage cells at both the protein ( Fig 8B) and mRNA level ( Fig 6A). Knockdown of BCL11B significantly reduced overall cellularity ( Fig 8C) and the frequency of CD3 + TCRab + thymocytes ( Fig 8D and E), but significantly increased the frequency of cd T cells ( Fig 8D and E).…”

Single cell profiling of immature human postnatal thymocytes resolves the complexity of intra-thymic lineage differentiation and thymus seeding precursors

“…BCL11B has also been shown to regulate human T-lineage commitment but its induction comes later compared to GATA3. This may suggest that GATA3 initiates T-lineage commitment while BCL11B rather enforces it (Ha et al, 2017;Li et al, 2013) . Strikingly, induction of TCF7 expression coincides with BCL11B induction which is much later compared to during murine T cell development (Weber et al, 2011) , indicating that the transcription factor networks that control these distinct stages of human T cell development are different compared to in mouse.…”

“…This coincides with a transient expression of other stem and progenitor genes such as HHEX and LYL1, and of SPI1 that suggests multi-lineage priming as recently described during murine T cell development (Zhou et al, 2019) . Differentiation into ETPs is also characterized by the upregulation of GATA3 which continues to increase in expression during the subsequent specification and commitment stages (Van de Walle et al, 2016) , but that clearly precedes expression of other critical T-lineage TFs such as TCF12 , TCF7 and BCL11B (Ha et al, 2017) ; and of the CD3 genes ( CD3D , CD3E…”

“…This is clearly exemplified by the differences in cell surface markers that are used to phenotype the most immature T cell precursors and this has obscured a clear comparison of these initial stages of T cell development across species. Also functional perturbation experiments have suggested that the molecular mechanisms driving early T cell development in human might differ compared to in mouse (Ha et al, 2017;Taghon et al, 2009;Van de Walle et al, 2009 .…”