SCL, LMO1 and Notch1 Reprogram Thymocytes into Self-Renewing Cells

Gerby, Bastien; Tremblay, Cédric; Tremblay, Mathieu; Rojas-Sutterlin, Shanti; Herblot, Sabine; Hébert, Josée; Sauvageau, Guy; Lemieux, Sébastien; Lécuyer, Éric; Veiga, Diogo F.T.; Hoang, Trang

doi:10.1371/journal.pgen.1004768

Cited by 59 publications

(80 citation statements)

References 119 publications

(179 reference statements)

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“…For example, the TAL1/SCL bHLH transcription factor is required for hematopoietic stem cell specification and self-renewal during development. TAL1/SCL is overexpressed in 60% of T-cell acute lymphoblastic leukemia (T-ALL) (Ferrando et al, 2002) and can reprogram thymocytes into self-renewing, pre-leukemic cells (Gerby et al, 2014). This same paradigm has also been seen in brain tumors.…”

Section: Discussionmentioning

confidence: 99%

Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma

Tenente

Hayes

Ignatius

et al. 2017

eLife

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Rhabdomyosarcoma (RMS) is a pediatric malignacy of muscle with myogenic regulatory transcription factors MYOD and MYF5 being expressed in this disease. Consensus in the field has been that expression of these factors likely reflects the target cell of transformation rather than being required for continued tumor growth. Here, we used a transgenic zebrafish model to show that Myf5 is sufficient to confer tumor-propagating potential to RMS cells and caused tumors to initiate earlier and have higher penetrance. Analysis of human RMS revealed that MYF5 and MYOD are mutually-exclusively expressed and each is required for sustained tumor growth. ChIP-seq and mechanistic studies in human RMS uncovered that MYF5 and MYOD bind common DNA regulatory elements to alter transcription of genes that regulate muscle development and cell cycle progression. Our data support unappreciated and dominant oncogenic roles for MYF5 and MYOD convergence on common transcriptional targets to regulate human RMS growth.DOI: http://dx.doi.org/10.7554/eLife.19214.001

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Section: Discussionmentioning

confidence: 99%

Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma

Tenente

Hayes

Ignatius

et al. 2017

eLife

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“…Subsequently, one of 23 functional V␤ (variable) mouse gene segments is joined to the previously rearranged D␤J␤ recombinant at the DN3 stage (thereby generating VDJ recombinants) to generate a Tcrb gene encoding the ␤ chain of the pre-TCR complex (6,17,18). A similar VDJ rearrangement is also observed during B cell development at the immunoglobulin heavy chain gene (Igh) locus.…”

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confidence: 99%

GATA3 Abundance Is a Critical Determinant of T Cell Receptor β Allelic Exclusion

Sekiguchi

Panwar

et al. 2017

Molecular and Cellular Biology

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Allelic exclusion describes the essential immunological process by which feedback repression of sequential DNA rearrangements ensures that only one autosome expresses a functional T or B cell receptor. In wild-type mammals, approximately 60% of cells have recombined the DNA of one T cell receptor ␤ (TCR␤) V-to-DJ-joined allele in a functional configuration, while the second allele has recombined only the DJ sequences; the other 40% of cells have recombined the V to the DJ segments on both alleles, with only one of the two alleles predicting a functional TCR␤ protein. Here we report that the transgenic overexpression of GATA3 leads predominantly to biallelic TCR␤ gene (Tcrb) recombination. We also found that wild-type immature thymocytes can be separated into distinct populations based on intracellular GATA3 expression and that GATA3 LO cells had almost exclusively recombined only one Tcrb locus (that predicted a functional receptor sequence), while GATA3 HI cells had uniformly recombined both Tcrb alleles (one predicting a functional and the other predicting a nonfunctional rearrangement). These data show that GATA3 abundance regulates the recombination propensity at the Tcrb locus and provide new mechanistic insight into the historic immunological conundrum for how Tcrb allelic exclusion is mediated.KEYWORDS allelic exclusion, T cell receptor beta locus, GATA3, monoallelic-tobiallelic switch O ne enduring mystery in cellular immunology regards the underlying mechanisms that control antigen receptor allelic exclusion (1, 2), the process whereby B or T lymphocytes are programmed to express only one functional allele for each chain of their respective antigen receptors (B cell receptor [BCR] or T cell receptor [TCR]), thus avoiding the coexistence of multiple antigen specificities in a single immune cell. Lymphocytes acquire the diversity of antigen recognition (3) as well as a unique monospecificity for particular antigens (4) during development in the bone marrow (B cells) or the thymus (T cells).T lymphocyte development is generally characterized by division into multiple stages based on developmental timing and the location and expression of specific cell surface markers (5). T cell development begins when multipotential hematopoietic progenitor cells in the bone marrow migrate through the bloodstream to the thymus, where early T lineage progenitors (ETPs) are generated and later specified to become T cells (6-10). ETPs differentiate into double-negative (DN) cells (DN2 to DN4 stages) that express neither the CD4 nor the CD8 coreceptor, then into double-positive (DP)

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“…Scale bar, 100 mm ( ÃÃÃ , P < 0.0006; Ã , P < 0.05; ns, not significant). (34,35). Homozygous Cbfa2t3-mutant mice also have lower numbers of T cells, with primary perturbations in the DN1 populations (29).…”

Section: Discussionmentioning

confidence: 99%

The Pluripotency Regulator PRDM14 Requires Hematopoietic Regulator CBFA2T3 to Initiate Leukemia in Mice

Tracey

Brooke-Bisschop

Jansen

et al. 2019

Molecular Cancer Research

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PR domain-containing 14 (Prdm14) is a pluripotency regulator central to embryonic stem cell identity and primordial germ cell specification. Genomic regions containing PRDM14 are often amplified leading to misexpression in human cancer. Prdm14 expression in mouse hematopoietic stem cells (HSC) leads to progenitor cell expansion prior to the development of T-cell acute lymphoblastic leukemia (T-ALL), consistent with PRDM14's role in cancer initiation. Here, we demonstrate mechanistic insight into PRDM14-driven leukemias in vivo. Mass spectrometry revealed novel PRDM14-protein interactions including histone H1, RNA-binding proteins, and the master hematopoietic regulator CBFA2T3. In mouse leukemic cells, CBFA2T3 and PRDM14 associate independently of the related ETO family member CBFA2T2, PRDM14's primary protein partner in pluripotent cells. CBFA2T3 plays crucial roles in HSC self-renewal and lineage commitment, and participates in oncogenic translocations in acute myeloid leukemia. These results suggest a model whereby PRDM14 recruits CBFA2T3 to DNA, leading to gene misregulation causing progenitor cell expansion and lineage perturbations preceding TALL development. Strikingly, Prdm14induced TALL does not occur in mice deficient for Cbfa2t3, demonstrating that Cbfa2t3 is required for leukemogenesis. Moreover, TALL develops in Cbfa2t3 heterozygotes with a significantly longer latency, suggesting that PRDM14-associated TALL is sensitive to Cbfa2t3 levels. Our study highlights how an oncogenic protein uses a native protein in progenitor cells to initiate leukemia, providing insight into PRDM14-driven oncogenesis in other cell types. Implications: The pluripotency regulator PRDM14 requires the master hematopoietic regulator CBFA2T3 to initiate leukemia in progenitor cells, demonstrating an oncogenic role for CBFA2T3 and providing an avenue for targeting cancerinitiating cells.

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SCL, LMO1 and Notch1 Reprogram Thymocytes into Self-Renewing Cells

Cited by 59 publications

References 119 publications

Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma

Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma

GATA3 Abundance Is a Critical Determinant of T Cell Receptor β Allelic Exclusion

The Pluripotency Regulator PRDM14 Requires Hematopoietic Regulator CBFA2T3 to Initiate Leukemia in Mice

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