title: 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.
authors.affiliation: Children's Center for Cancer and Blood Disease, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: V L
authors.initials: VL
authors.lastname: Ha
authors.affiliation: Children's Center for Cancer and Blood Disease, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Luong
authors.affiliation: MiNGS Core Laboratory, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: D
authors.identifier: 0000-0002-7347-3330
authors.initials: D
authors.lastname: Casero
authors.affiliation: Children's Center for Cancer and Blood Disease, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Malvar
authors.affiliation: Children's Center for Cancer and Blood Disease, Children's Hospital Los Angeles, Los Angeles, CA, USA.|Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Y M
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bhatia
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, CA, USA.|Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA.|Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA.|Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Crooks
authors.affiliation: Children's Center for Cancer and Blood Disease, Children's Hospital Los Angeles, Los Angeles, CA, USA.|Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Parekh
mesh_terms: D002454:Cell Differentiation / Q000235:genetics*; D006801:Humans; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D013601:T-Lymphocytes / Q000166:cytology*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C479740:BCL11B protein, human; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins