GATA3 induces human T-cell commitment by restraining Notch activity and repressing NK-cell fate

Walle, Inge Van de; Dolens, Anne-Catherine; Durinck, Kaat; Mulder, Katrien De; Loocke, Wouter Van; Damle, Sagar S.; Waegemans, Els; Medts, Jelle De; Velghe, Imke; Smedt, Magda De; Vandekerckhove, Bart; Kerre, Tessa; Plum, Jean; Leclercq, Georges; Rothenberg, Ellen V.; Vlierberghe, Pieter Van; Speleman, Frank; Taghon, Tom

doi:10.1038/ncomms11171

Cited by 59 publications

(80 citation statements)

References 49 publications

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“…KD cells showed upregulation of hematopoietic stem and progenitor ( BAALC , GFI1B , HOXA9, CD34) and myeloid ( MEF2C , MPO ) genes and downregulation of T-lineage genes ( PTCRA , RAG1 , RAG2 , LCK , ZAP70 , THEMIS ). Also, KD induced upregulation of genes important for NK cell development ( DTX1 ) 12 and function ( ZBTB16 ) 40 , and downregulation of IL7R , a gene critical for T-cell differentiation. NOTCH1 signaling is known to be decreased during human T-lineage commitment 12 ; KD cells, however, showed upregulation of NOTCH1 target genes ( DTX1 , NRARP , MYC ) 12 (Figure 5a,b).…”

Section: Resultsmentioning

confidence: 99%

“…Also, KD induced upregulation of genes important for NK cell development ( DTX1 ) 12 and function ( ZBTB16 ) 40 , and downregulation of IL7R , a gene critical for T-cell differentiation. NOTCH1 signaling is known to be decreased during human T-lineage commitment 12 ; KD cells, however, showed upregulation of NOTCH1 target genes ( DTX1 , NRARP , MYC ) 12 (Figure 5a,b). Overall, KD resulted in downregulation of genes that are normally induced with T-lineage commitment, and the aberrantly sustained expression of a transcriptional program characteristic of the earliest stage of human thymopoiesis (Thy1, CD34+CD7−CD1a−) (Figure 5a,b, Supplementary Figure 6a,b).…”

Section: Resultsmentioning

confidence: 99%

“…Functional studies have yielded key insights about the mechanisms underlying murine T-lineage commitment 9 . However, critical immunophenotypic and regulatory differences between murine and human thymopoiesis have been recognized 2,10,11,12 , and there are few studies of the molecular processes mediating human T-lineage commitment. Thus, our understanding of the regulation of the initial stages of human thymopoiesis is incomplete.…”

Section: Introductionmentioning

confidence: 99%

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

Luong

et al. 2017

Leukemia

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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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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Luong

et al. 2017

Leukemia

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“…These findings have numerous implications since p27 is present in many different cell and tissue types and important in development, aging, and cancer, where cell differentiation is an important process (Chu et al, 2008; Pruitt et al, 2013; Teratake et al, 2016). Similarly, GATA3 is a critical transcription factor in many cell types and cell processes including T-cell differentiation, neurosensory development, and tumor progression and metastasis (Du et al, 2015; Duncan and Fritzsch, 2013; Si et al, 2015; Van de Walle et al, 2016). If, and how, p27 regulates GATA3 expression in these and other cells, tissues, and processes therefore remain intriguing and open questions.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Interplay between p27Kip1, GATA3, ATOH1, and POU4F3 Converts Non-sensory Cells to Hair Cells in Adult Mice

Walters¹,

Coak²,

Dearman³

et al. 2017

Cell Reports

127

164

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SUMMARY Hearing loss is widespread and persistent because mature mammalian auditory hair cells (HCs) are nonregenerative. In mice, the ability to regenerate HCs from surrounding supporting cells (SCs) declines abruptly after postnatal maturation. We find that combining p27Kip1 deletion with ectopic ATOH1 expression surmounts this age-related decline, leading to conversion of SCs to HCs in mature mouse cochleae and after noise damage. p27Kip1 deletion, independent of canonical effects on Rb-family proteins, upregulated GATA3, a co-factor for ATOH1 that is lost from SCs with age. Co-activation of GATA3 or POU4F3 and ATOH1 promoted conversion of SCs to HCs in adult mice. Remarkably, activation of POU4F3 alone also converted mature SCs to HCs in vivo. These data illuminate a genetic pathway that initiates auditory HC regeneration and suggest p27Kip1, GATA3, and POU4F3 as additional therapeutic targets for Atoh1-mediated HC regeneration.

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“…The up-regulation of GATA3 has been also associated with cancers some being of hematopoietic origin [58]. GATA3 is a transcription factor involved in the development of lymphocytes, particularly favoring a Th2 response [59,60]. Increased expression of GATA3 has been shown to be a good prognosis marker in other types of cancer such as breast.…”

Section: Discussionmentioning

confidence: 99%

IL-15 regulates migration, invasion, angiogenesis and genes associated with lipid metabolism and inflammation in prostate cancer

et al. 2017

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Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer. In the United States it is second leading cause of cancer related deaths in men. PCa is often treated via radical prostatectomy (RP). However, 15–30% of the patients develop biochemical recurrence (i.e. increased serum prostate specific antigen (PSA) levels). Interleukin-15 (IL-15) is a secreted cytokine found over expressed in patients with recurrence-free survival after RP. In our study, we aim to determine the role of IL-15 in PCa using in vitro and in vivo models, and gene expression analysis. PC3 (androgen-independent) and 22RV1 (androgen-dependent) cell lines were treated with IL-15 at 0.0013 ng/mL and 0.1 ng/mL. Tumor growth was evaluated using an orthotopic xenograft model. The anterior prostate lobes of SCID mice were injected with 250,000 22RV1 cells and IL-15 was administered bi-weekly with intraperitoneal (IP) injections during 4 weeks. Tumor tissue was collected for immunohistochemical and gene expression analysis. To study changes in gene expression, we looked at “Tumor Metastasis” and “PI3K pathway” using commercially available PCR arrays. In addition, we employed a microarray approach using the Affymetrix Hugene 2.0 ST array chip followed by analysis with Ingenuity Pathways Analysis (IPA) software. In vitro studies showed that IL-15 decreased PCa cell motility at both concentrations. In vivo studies showed that IL-15 increased neutrophil infiltration, and the expression of adiponectin, desmin and alpha smooth muscle actin (α-sma) in the tumor tissue. Angiogenesis analysis, using CD31 immunohistochemistry, showed that IL-15 decreased the number of blood vessels. Gene expression analysis identified Cancer, Cell Death, Immune Response and Lipid Metabolism as the major diseases and functions altered in tumors treated with IL-15. This suggests that IL-15 causes inflammation and changes in stroma that can promote decreased tumor cell proliferation.

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GATA3 induces human T-cell commitment by restraining Notch activity and repressing NK-cell fate

Cited by 59 publications

References 49 publications

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

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

In Vivo Interplay between p27Kip1, GATA3, ATOH1, and POU4F3 Converts Non-sensory Cells to Hair Cells in Adult Mice

IL-15 regulates migration, invasion, angiogenesis and genes associated with lipid metabolism and inflammation in prostate cancer

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