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

Academic Article

Abstract

  • © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. 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.
  • Published In

  • Leukemia  Journal
  • Digital Object Identifier (doi)

    Author List

  • Ha VL; Luong A; Li F; Casero D; Malvar J; Kim YM; Bhatia R; Crooks GM; Parekh C
  • Start Page

  • 2503
  • End Page

  • 2514
  • Volume

  • 31
  • Issue

  • 11