Developmental gene networks: a triathlon on the course to T cell identity

Abstract

Summary Cells acquire their ultimate identities by activating combinations of transcription factors that initiate and sustain expression of the appropriate cell-type specific genes. T-cell development depends on the progression of progenitor cells through three major phases associated with distinct transcription factor ensembles that control their recruitment to and proliferation in the thymus, their lineage commitment, and their responsiveness to T-cell receptor (TCR) signals, before the allocation of cells to particular effector programs. All three phases are essential for proper T cell development, as are the mechanisms that determine the boundaries between each phase: cells failing to shut off one set of regulators before the next gene network phase is activated are predisposed to leukemic transformation.

Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network

“…5). If the precursors can begin TCR expression successfully in DN3a, they continue through DN3b and DN4 to DP, when the cells finally acquire complete TCR recognition complexes (5,6). Importantly, if individual T-cell precursors in the ETP or DN2a stage are removed from thymic Notch ligands, they can still generate non-T cells, but from the DN2b stage on, they can no longer do this unless genetically manipulated (1,7).…”

“…In fact, many of the new Bcl11b target genes are unique to the pericommitment developmental context. We place these findings in the context of an updated version of the T-cell specification GRN model (5,(18)(19)(20) enhanced with recent insights into connections between PU.1, Bcl11b, Notch signaling, and other crucial factors: that is, GATA-3, TCF-1, Runx1, and the basic helixloop-helix factor E2A.…”

“…The resulting Notch signaling drives precursors to proliferate through a canonical series of stages [double negative (DN) = CD4 − CD8 − ; double positive (DP) = CD4 + CD8 + ]: from Kit hi DN1 (or early T-cell precursor, ETP), to DN2a, DN2b, and DN3a stage (reviewed in ref. 5). If the precursors can begin TCR expression successfully in DN3a, they continue through DN3b and DN4 to DP, when the cells finally acquire complete TCR recognition complexes (5,6).…”

“…The robust change in potential from DN2a to DN2b is also accompanied by dynamic transcription factor expression changes (8,9) At least 20 regulatory genes have expression patterns that can be classed as "phase 1" (expressed in ETP and DN2a, then down-regulated) or "phase 2" (turned on or significantly upregulated around commitment in DN2b) (5). To date, the moststudied regulators of the phase 1 to phase 2 transition have been Notch signaling, GATA-3, TCF-1, and E2A, and PU.1 as a natural, endogenous "opponent" of developmental progression.…”

Role of a non-canonical splice variant of the Helios gene in the differentiation of acute lymphoblastic leukemic T cells

“…The transcription factors, such as Notch1, E2A, Id proteins, Ikaros, and PU.1 perform definitive functions in the T-cell differentiation (1). Along the pathway of commitment and maturation, the early T-cell precursors upregulate the expressions of the transcription factors, such as Notch1, Ikaros, GATA3, and Runx1.…”