Homozygous deletions and point mutations of the Rit1/Bcl11b gene in γ-ray induced mouse thymic lymphomas

Wakabayashi, Yuichi; Inoue, Jun; Takahashi, Yoshiaki; Matsuki, Atsushi; Kosugi-Okano, Hitomi; Shinbo, Toshimitsu; Mishima, Yukio; Niwa, Ohtsura; Kominami, Ryo

doi:10.1016/s0006-291x(02)03069-3

Cited by 112 publications

(130 citation statements)

References 29 publications

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“…Further translocations involving the BCL11B locus were reported in three T-ALL-derived cell lines and in one case of acute myelocytic leukemia Nagel et al, 2003;Bezrookove et al, 2004). In mice, deletions within BCL11B were found in normal thymocytes and in irradiation-induced lymphomas (Wakabayashi et al, 2003a;Sakata et al, 2004). We and others reported high levels of BCL11B mRNA expression in the majority of T-ALL and T-cell leukemia/lymphoma cell lines Przybylski et al, 2005).…”

Section: Introductionmentioning

confidence: 55%

“…Inhibition of BCL11B leads to apoptosis P Grabarczyk et al provided by the same group, who demonstrated deletions in the BCL11B locus in g-irradiation-induced lymphomas in mice (Wakabayashi et al, 2003a). The deletions were later found in normal thymocytes and occurred with same frequency in g-irradiated and nonirradiated mice, indicating rather an indirect role of BCL11B mutations in lymphomagenesis (Sakata et al, 2004) Interestingly, the deletions occurred with much higher frequencies in p53-proficient than in p53-deficient lymphomas, which suggested that loss of BCL11B might contribute to oncogenesis only in p53-proficient lymphocytes or was not required any more in p53-null lymphomas.…”

Section: Discussionmentioning

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: Introductionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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“…Bcl11b is a critical developmental protein. Studies on Bcl11b null mice, which die shortly after birth of unknown causes, have demonstrated important roles for Bcl11b in the immune system, where it controls T cell subtype specification and survival in the developing thymus (Wakabayashi et al, 2003). Studies in the CNS have demonstrated essential roles in the development of corticospinal motor neurons (Arlotta et al, 2005), and the differentiation of medium spiny neurons and establishment of cellular architecture of the striatum (Arlotta et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Functional roles for the striatal-enriched transcription factor, Bcl11b, in the control of striatal gene expression and transcriptional dysregulation in Huntington's disease

Desplats

Lambert

Thomas

2008

Neurobiology of Disease

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Transcriptional dysregulation has emerged as a central pathogenic mechanism in Huntington's disease (HD), which is associated with neuropathological changes predominantly in the striatum. Here we demonstrate that expression of Bcl11b (a.k.a. CTIP2), a transcription factor exhibiting highly-enriched localization in adult striatum, is significantly decreased in HD cells, mouse models and human subjects and that overexpression of Bcl11b attenuates toxic effects of mutant huntingtin in cultured striatal neurons. We show that Bcl11b directly activates the proximal promoter regions of striatal-enriched genes and can increase mRNA levels of striatal-expressing genes. We further demonstrate an interaction between Bcl11b and huntingtin protein in cultured cells and brain homogenates from HD R6/1 and YAC72 transgenic mice. We propose that sequestration and/or decreased expression of Bcl11b in HD is responsible, at least in part, for the dysregulation of striatal gene expression observed in HD and may contribute to the specificity of pathology observed in this disease.

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“…Due to the paucity of data in this area, in the present study, we investigated the effect of low-dose radiation exposure on accumulation of DNA lesions and alterations of DNA and histone methylation in thymus tissue using an in vivo murine model (31)(32)(33). Radiation exposure induces leukemia and lymphoma in rodents; therefore, the rodent model has become a valuable system for delineating molecular mechanisms of radiationinduced leukemia and lymphoma predisposition (31)(32)(33).…”

Section: Introductionmentioning

confidence: 99%

“…Radiation exposure induces leukemia and lymphoma in rodents; therefore, the rodent model has become a valuable system for delineating molecular mechanisms of radiationinduced leukemia and lymphoma predisposition (31)(32)(33).…”

Section: Introductionmentioning

confidence: 99%

Fractionated Low-Dose Radiation Exposure Leads to Accumulation of DNA Damage and Profound Alterations in DNA and Histone Methylation in the Murine Thymus

Pogribny

Koturbash

Tryndyak

et al. 2005

Molecular Cancer Research

149

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Thymus, an important component of hematopoietic tissue, is a well-documented ''target'' of radiation carcinogenesis. Both acute and fractionated irradiation result in a high risk of leukemia and thymic lymphoma. However, the exact mechanisms underlying radiation-induced predisposition to leukemia and lymphoma are still unknown, and the contributions of genetic and epigenetic mechanisms in particular have yet to be defined. Global DNA hypomethylation is a well-known characteristic of cancer cells. Recent studies have also shown that tumor cells undergo prominent changes in histone methylation, particularly a substantial loss of trimethylation of histone H4-Lys 20 and demethylation of genomic DNA. These losses are considered a universal marker of malignant transformation. In the present study, we investigated the effect of low-dose radiation exposure on the accumulation of DNA lesions and alterations of DNA methylation and histone H4-Lys 20 trimethylation in the thymus tissue using an in vivo murine model. For the first time, we show that fractionated whole-body application of 0.5 Gy X-ray leads to decrease in histone H4-Lys 20 trimethylation in the thymus. The loss of histone H4-Lys 20 trimethylation was accompanied by a significant decrease in global DNA methylation as well as the accumulation of DNA damage as monitored by persistence of histone ;H2AX foci in the thymus tissue of mice exposed to fractionated irradiation. Altered DNA methylation was associated with reduced expression of maintenance (DNMT1) and, to a lesser extent, de novo DNA methyltransferase DNMT3a in exposed animals. Expression of another de novo DNA methyltransferase DNMT3b was decreased only in males. Irradiation also resulted in f20% reduction in the levels of methyl-binding proteins MeCP2 and MBD2. Our results show the involvement of epigenetic alterations in radiation-induced responses in vivo. These changes may play a role in genome destabilization that ultimately leads to cancer. (Mol Cancer Res 2005;3(10):553 -61)

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Homozygous deletions and point mutations of the Rit1/Bcl11b gene in γ-ray induced mouse thymic lymphomas

Cited by 112 publications

References 29 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

Functional roles for the striatal-enriched transcription factor, Bcl11b, in the control of striatal gene expression and transcriptional dysregulation in Huntington's disease

Fractionated Low-Dose Radiation Exposure Leads to Accumulation of DNA Damage and Profound Alterations in DNA and Histone Methylation in the Murine Thymus

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