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Transcriptional control and signal transduction, cell cycle

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

Leukemia volume 31, pages 2503–2514 (2017)Cite this article

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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.

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Acknowledgements

We thank A George and Jonathan Kirzner for technical assistance; Dr Sara Twogood and Dr Wittenberg (Hollywood Presbyterian Hospital) for collecting CB; the Cardiothoracic Surgery Department at the Children’s Hospital Los Angeles (CHLA) for collecting thymuses; the CHLA Next generation sequencing core; CHLA and the Broad Stem Cell Research Center flow cytometry facilities; the Center for AIDS Research Virology Core Lab (supported by the US National Institutes of Health (AI-28697), the UCLA AIDS Institute and the UCLA Council of Bioscience Resources) for CB and reagents; Dr D Kohn for the MND-PGK-GFP plasmid; Dr D Trono for psPAX2, pMD2.G and pLVTHM plasmids; Dr D Sabatini for the scramble shRNA plasmid; and Dr Zuniga-Pflucker for the OP9-DLL1 cell line. This work was supported by the St Baldrick’s Foundation (CP), the US National Institutes of Health (K12 HD052954, K12 HD034610 and P30CA014089 to CP; P01 HL073104 to GMC; R01 CA172896 to YMK), the Nautica Foundation (CP), the Tower Cancer Research Foundation (CP), the Couples Against Leukemia Foundation (CP), the Joseph Drown Foundation (CP) and the UCLA Broad Stem Cell Research Center (GMC and DC).

Author contributions

VLH: collection and assembly of data (performance of experiments), data analysis and interpretation; AL: collection and assembly of data (performance of experiments), data analysis and interpretation; FL: bioinformatic analysis of RNA-Seq and ChIP-Seq data; DC: bioinformatic analysis of RNA-Seq data from normal bone marrow and thymic progenitors and assembly of annotated lncRNA database; JM: statistical analysis; YMK: generation of T-ALL xenograft; RB: conception and design, data analysis and interpretation; GMC: conception and design, data analysis and interpretation, manuscript writing; CP: conception and design, collection and assembly of data (performance of experiments), data analysis and interpretation, manuscript writing and final approval of manuscript.

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Authors and Affiliations

  1. Children’s Center for Cancer and Blood Disease, Children’s Hospital Los Angeles, Los Angeles, CA, USA

    V L Ha, A Luong, J Malvar, Y M Kim & C Parekh

  2. MiNGS Core Laboratory, Children’s Hospital Los Angeles, Los Angeles, CA, USA

    F Li

  3. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, CA, USA

    D Casero & G M Crooks

  4. Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Y M Kim & C Parekh

  5. Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    R Bhatia

  6. Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA

    G M Crooks

  7. Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA

    G M Crooks

  8. Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA

    G M Crooks

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  1. V L Ha
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Ha, V., Luong, A., Li, F. et al. The T-ALL related gene BCL11B regulates the initial stages of human T-cell differentiation. Leukemia 31, 2503–2514 (2017). https://doi.org/10.1038/leu.2017.70

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