Bcl11b is required for differentiation and survival of αβ T lymphocytes

Wakabayashi, Yuichi; Watanabe, Hirotaka; Inoue, Jun; Takeda, Nobuo; Sakata, Jun; Mishima, Yukio; Hitomi, Jiro; Yamamoto, Takashi; Utsuyama, Masanori; Niwa, Ohtsura; Aizawa, Shinichi; Kominami, Ryo

doi:10.1038/ni927

Cited by 310 publications

(353 citation statements)

References 44 publications

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“…Reduction of BCL11B expression resulted in dramatically increased apoptosis in both T-cell leukemia and lymphoma cell lines. This is consistent with the findings of Wakabayashi et al (2003b), who detected elevated apoptosis in the thymuses of neonatal BCL11B knockout mice. The pro-apoptotic effect of BCL11B deficiency was pronounced and led to the complete block of thymopoiesis in the early stages in these animals.…”

Section: Discussionsupporting

confidence: 93%

“…The lack of BCL11B expression in knockout mice completely blocks the differentiation of ab T lymphocytes (Wakabayashi et al, 2003b). The authors hypothesized that this could be due to the pronounced sensitivity of thymocytes to apoptotic signals, a lack of pre-T-cell receptor (TCR) signaling, or a functional impairment of parallel pro-survival pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Lack of BCL11B, as shown in germline knockout mice, leads to abnormal thymopoiesis and the complete absence of mature ab T cells (Wakabayashi et al, 2003b). Specifically, the transition from the double-negative stage 3 (DN3) to DN4 stage was blocked, the rearrangement of T-cell receptor b locus (TRB) was incomplete and extensive apoptosis was observed.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of BCL11B expression leads to apoptosis of malignant but not normal mature T cells

et al. 2006

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The B-cell chronic lymphocytic leukemia (CLL)/lymphoma 11B gene (BCL11B) encodes a Kru¨ppel-like zincfinger protein, which plays a crucial role in thymopoiesis and has been associated with hematopoietic malignancies. It was hypothesized that BCL11B may act as a tumorsuppressor gene, but its precise function has not yet been elucidated. Here, we demonstrate that the survival of human T-cell leukemia and lymphoma cell lines is critically dependent on Bcl11b. Suppression of Bcl11b by RNA interference selectively induced apoptosis in transformed T cells whereas normal mature T cells remained unaffected. The apoptosis was effected by simultaneous activation of death receptor-mediated and intrinsic apoptotic pathways, most likely as a result of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) upregulation and suppression of the Bcl-xL antiapoptotic protein. Our data indicate an antiapoptotic function of Bcl11b. The resistance of normal mature T lymphocytes to Bcl11b suppression-induced apoptosis and restricted expression pattern make it an attractive therapeutic target in T-cell malignancies.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of BCL11B expression leads to apoptosis of malignant but not normal mature T cells

et al. 2006

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“…Nrn1 has been described to protect cells from apoptosis, by inhibiting activation of caspase 3 [41]. Further antiapoptotic genes with reduced activity in Hopx À/À Th1 cells were Bcl11b [42], Gna13 (Galpha13) [43] and Hsp90ab1 [44,45] (Supporting Information Fig. 6).…”

Section: Hopx Regulates Expression Of Apoptotic Genes and Lowers Sensmentioning

confidence: 99%

Persistence of effector memory Th1 cells is regulated by Hopx

et al. 2010

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Th1 cells are prominent in inflamed tissue, survive conventional immunosuppression, and are believed to play a pivotal role in driving chronic inflammation. Here, we identify homeobox only protein (Hopx) as a critical and selective regulator of the survival of Th1 effector/memory cells, both in vitro and in vivo. Expression of Hopx is induced by T-bet and increases upon repeated antigenic restimulation of Th1 cells. Accordingly, the expression of Hopx is low in peripheral, naïve Th cells, but highly up-regulated in terminally differentiated effector/memory Th1 cells of healthy human donors. In murine Th1 cells, Hopx regulates the expression of genes involved in regulation of apoptosis and survival and makes them refractory to Fas-induced apoptosis. In vivo, adoptively transferred Hopxdeficient murine Th1 cells do not persist. Consequently, they cannot induce chronic inflammation in murine models of transfer-induced colitis and arthritis, demonstrating a key role of Hopx for Th1-mediated immunopathology.Key words: Cell survival . CD4 T cells . Inflammation . Memory cells Supporting Information available onlineIntroduction T-helper type 1 (Th1) cells mediate immune responses to intracellular pathogens, such as viruses, and produce IFN-g as their signature cytokine [1]. IFN-g, together with IL-12 and the transcription factors STAT1, STAT4 and T-bet, promotes the development of Th1 cells [2][3]. T-bet (T-box 21) is considered to act as the master transcription factor critically regulating Th1 lineage commitment [3][4][5]. Apart from their protective role in clearing infections, Th1 cells can initiate and maintain chronic inflammatory diseases, e.g. inflammatory bowel disease [6][7][8][9], uveitis [10], EAE [11,12] and arthritis [13]. In vitro, Th1 cells are much more sensitive to Fas-mediated apoptosis than Th2 or Th17 cells [14][15][16][17][18][19][20]. In vivo, however, effector/memory Th1 cells are abundant in chronically inflamed tissue [21][22][23] and persist over long time periods [24][25][26], suggesting that their sensitivity to Eur. J. Immunol. 2010. 40: 2993-3006 DOI 10.1002 HIGHLIGHTS 2993 FrontlineFas-mediated apoptosis is strictly regulated. Here, we demonstrate that among CD4 1 T cells, the transcriptional cofactor homeobox only protein (Hopx) is expressed by repeatedly restimulated Th1 cells, but not by Th2, Th17 or regulatory T cells. Hopx regulates Fas-mediated apoptosis of effector/memory Th1 cells and is critically required for their persistence in vivo.In vertebrates, Hopx expression originally was detected in the myocardium [27,28]. There, expression of Hopx is induced by the cardiac transcription factor Nkx2-5. Hopx-deficient mice show a complex, incompletely penetrant phenotype. Some Hopxdeficient embryos have a poorly developed myocardium with reduced cell numbers, others show normal, and still others show increased numbers of cardiomyocytes after birth [27,28]. Hopx does not bind to homeobox consensus binding sequences, and it has been postulated that Hopx acts indirectly, partnering with ...

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“…10 It is expressed in T cells, thymocytes and in the brain. 11,12 Wakabayashi et al 13 recently demonstrated that BCL11B plays a key role in differentiation and survival during T-cell development in mice. This paper describes for the first time the sequence of the breakpoint of a chromosomal aberration that disrupts the BCL11B gene through fusion to TCRD in T-ALL and results in the expression of the BCL11B-TRDC fusion transcripts.…”

Section: Introductionmentioning

confidence: 99%

Disruption of the BCL11B gene through inv(14)(q11.2q32.31) results in the expression of BCL11B-TRDC fusion transcripts and is associated with the absence of wild-type BCL11B transcripts in T-ALL

et al. 2005

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T-cell acute lymphoblastic leukemia (T-ALL) is associated with chromosomal aberrations characterized by juxtaposition of proto-oncogenes to T-cell receptor gene loci (TCR), resulting in the deregulated transcription of these proto-oncogenes. Here, we describe the molecular characterization of a novel chromosomal aberration, inv(14)(q11.2q32.31), in a T-ALL sample, involving the recently described BCL11B gene and the TCRD locus. The inversion joined the 5 0 part of BCL11B, including exons 1-3, to the TRDD3 gene segment of the TCRD locus, whereas the reciprocal breakpoint fused the TRDV1 gene segment to the fourth exon of BCL11B. The TRDV1-BCL11B joining region was 1344 bp long and contained fragments derived from 20q11.22, 3p21.33 and from 11p12, indicating the complex character of this aberration. A strong expression of inframe transcripts with truncated BCL11B and TCRD constant region (TRDC) were observed, but in contrast to normal T cells and other T-ALL samples, no wild-type BCL11B transcripts were detected in the T-ALL sample. Screening of 37 other T-ALLs revealed one additional case with expression of the BCL11B-TRDC fusion transcript. As BCL11B appears to play a key role in T-cell differentiation, BCL11B disruption and disturbed expression may contribute to the development of T-cell malignancies in man.

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Bcl11b is required for differentiation and survival of αβ T lymphocytes

Cited by 310 publications

References 44 publications

Inhibition of BCL11B expression leads to apoptosis of malignant but not normal mature T cells

Inhibition of BCL11B expression leads to apoptosis of malignant but not normal mature T cells

Persistence of effector memory Th1 cells is regulated by Hopx

Disruption of the BCL11B gene through inv(14)(q11.2q32.31) results in the expression of BCL11B-TRDC fusion transcripts and is associated with the absence of wild-type BCL11B transcripts in T-ALL

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