Reduced Level of the BCL11B Protein Is Associated with Adult T-Cell Leukemia/Lymphoma

Kurosawa, Nobuyuki; Fujimoto, Rika; Ozawa, Tatsuhiko; Itoyama, Takahiro; Sadamori, Naoki; Isobe, Masaharu

doi:10.1371/journal.pone.0055147

Cited by 18 publications

(12 citation statements)

References 39 publications

(39 reference statements)

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“…Kurosawa et al . 18 showed that the BCL11B expression levels in HTLV-1-infected cells were downregulated relative to those in HTLV-1-infected cells. To elucidate the mechanism responsible for this, we measured the expression of BCL11B in various human T-cell lines, including HTLV-1-transformed and ATL-derived cell lines by performing western blot analyses and RT-PCR assays.…”

Section: Resultsmentioning

confidence: 99%

“…Genetic alterations of BCL11B, such as by chromosomal rearrangements, have been identified in several T-ALL patients. 17 Intriguingly, HTLV-1-infected T-cells, including ATL cells, have been reported to have reduced BCL11B protein expression, 18 but the mechanism remains to be elucidated. In the present study, we show that the HTLV-1 oncoprotein Tax is sufficient to downregulate BCL11B expression in T-cells.…”

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confidence: 99%

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Human T‐cell leukemia virus type 1 Tax oncoprotein represses the expression of the BCL11B tumor suppressor in T‐cells

et al. 2015

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Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia (ATL), which is an aggressive form of T-cell malignancy. HTLV-1 oncoproteins, Tax and HBZ, play crucial roles in the immortalization of T-cells and/or leukemogenesis by dysregulating the cellular functions in the host. Recent studies show that HTLV-1-infected T-cells have reduced expression of the BCL11B tumor suppressor protein. In the present study, we explored whether Tax and/or HBZ play a role in downregulating BCL11B in HTLV-1-infected T-cells. Lentiviral transduction of Tax in a human T-cell line repressed the expression of BCL11B at both the protein and mRNA levels, whereas the transduction of HBZ had little effect on the expression. Tax mutants with a decreased activity for the NF-κB, CREB or PDZ protein pathways still showed a reduced expression of the BCL11B protein, thereby implicating a different function of Tax in BCL11B downregulation. In addition, the HTLV-2 Tax2 protein reduced the BCL11B protein expression in T-cells. Seven HTLV-1-infected T-cell lines, including three ATL-derived cell lines, showed reduced BCL11B mRNA and protein expression relative to an uninfected T-cell line, and the greatest reductions were in the cells expressing Tax. Collectively, these results indicate that Tax is responsible for suppressing BCL11B protein expression in HTLV-1-infected T-cells; Tax-mediated repression of BCL11B is another mechanism that Tax uses to promote oncogenesis of HTLV-1-infected T-cells.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Human T‐cell leukemia virus type 1 Tax oncoprotein represses the expression of the BCL11B tumor suppressor in T‐cells

et al. 2015

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“…Further clarification is needed as reduced Bcl11b expression has been associated both with promotion and apoptosis of T cell leukemia and lymphoma [72, 73]. Although Bcl11b +/− mice are known to be more susceptible to radiation-induced thymic lymphomas, may undergo modest T cell developmental arrest, and have elevated levels of proliferative βcatenin despite reduced preTCR signaling [48, 74], in the absence of other mutations a single wild-type allele appears sufficient to prevent cell transformation.…”

Section: Discussionmentioning

confidence: 99%

Illegitimate V(D)J recombination-mediated deletions in Notch1 and Bcl11b are not sufficient for extensive clonal expansion and show minimal age or sex bias in frequency or junctional processing

Champagne

Shockett

2014

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Illegitimate V(D)J recombination at oncogenes and tumor suppressor genes is implicated in formation of several T cell malignancies. Notch1 and Bcl11b, genes involved in developing T cell specification, selection, proliferation, and survival, were previously shown to contain hotspots for deletional illegitimate V(D)J recombination associated with radiation-induced thymic lymphoma. Interestingly, these deletions were also observed in wild-type animals. In this study, we conducted frequency, clonality, and junctional processing analyses of Notch1 and Bcl11b deletions during mouse development and compared results to published analyses of authentic V(D)J rearrangements at the T cell receptor beta (TCRβ) locus and illegitimate V(D)J deletions observed at the human, nonimmune HPRT1 locus not involved in T cell malignancies. We detect deletions in Notch1 and Bcl11b in thymic and splenic T cell populations, consistent with cells bearing deletions in the circulating lymphocyte pool. Deletions in thymus can occur in utero, increase in frequency between fetal and postnatal stages, are detected at all ages examined between fetal and 7 months, exhibit only limited clonality (contrasting with previous results in radiation-sensitive mouse strains), and consistent with previous reports are more frequent in Bcl11b, partially explained by relatively high Recombination Signal Information Content (RIC) scores. Deletion junctions in Bcl11b exhibit greater germline nucleotide loss, while in Notch1 palindromic (P) nucleotides are more abundant, although average P nucleotide length is similar for both genes and consistent with results at the TCRβ locus. Non-templated (N) nucleotide insertions appear to increase between fetal and postnatal stages for Notch1, consistent with normal terminal deoxynucleotidyl transferase (TdT) activity; however, neonatal Bcl11b junctions contain elevated levels of N insertions. Finally, contrasting with results at the HPRT1 locus, we find no obvious age or gender bias in junctional processing, and inverted repeats at recessed coding ends (Pr nucleotides) correspond mostly to single-base additions consistent with normal TdT activity.

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“…Bcl11b has been observed as a target of the mir-17 cluster (Lewis et al, 2003; Zeller et al, 2003) as well as miR-93 and let-7 in T cells (Kurosawa et al, 2013). Given the accumulating data of the importance of Bcl11b in critical brain regions such as hippocampus, the expression of microRNAs targeting Bcl11b in the hippocampus is a fertile area for further study.…”

Section: Neuronal Expression Of Bcl11b In Development and Adulthoodmentioning

confidence: 99%

Bcl11b—A Critical Neurodevelopmental Transcription Factor—Roles in Health and Disease

Lennon

Jones

Lovelace

et al. 2017

Front. Cell. Neurosci.

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B cell leukemia 11b (Bcl11b) is a zinc finger protein transcription factor with a multiplicity of functions. It works as both a genetic suppressor and activator, acting directly, attaching to promoter regions, as well as indirectly, attaching to promoter-bound transcription factors. Bcl11b is a fundamental transcription factor in fetal development, with important roles for the differentiation and development of various neuronal subtypes in the central nervous system (CNS). It has been used as a specific marker of layer V subcerebral projection neurons as well as striatal interneurons. Bcl11b also has critical developmental functions in the immune, integumentary and cardiac systems, to the extent that Bcl11b knockout mice are incompatible with extra-uterine life. Bcl11b has been implicated in a number of disease states including Huntington's disease, Alzheimer's disease, HIV and T-Cell malignancy, amongst others. Bcl11b is a fascinating protein whose critical roles in the CNS and other parts of the body are yet to be fully explicated. This review summarizes the current literature on Bcl11b and its functions in development, health, and disease as well as future directions for research.

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Reduced Level of the BCL11B Protein Is Associated with Adult T-Cell Leukemia/Lymphoma

Cited by 18 publications

References 39 publications

Human T‐cell leukemia virus type 1 Tax oncoprotein represses the expression of the BCL11B tumor suppressor in T‐cells

Human T‐cell leukemia virus type 1 Tax oncoprotein represses the expression of the BCL11B tumor suppressor in T‐cells

Illegitimate V(D)J recombination-mediated deletions in Notch1 and Bcl11b are not sufficient for extensive clonal expansion and show minimal age or sex bias in frequency or junctional processing

Bcl11b—A Critical Neurodevelopmental Transcription Factor—Roles in Health and Disease

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