Early Thymocyte Development Is Regulated by Modulation of E2a Protein Activity

Engel, Isaac; Johns, Carol; Bain, Gretchen; Rivera, Richard; Murre, Cornelis

doi:10.1084/jem.194.6.733

Cited by 168 publications

(224 citation statements)

References 46 publications

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“…E2A null mutant mice spontaneously developed monoclonal T lymphoma in thymus between 3 ± 6 months, preceded by a decreased percentage of CD44 low CD25 + cells and increased percentage of CD44 high CD25 7 DN cell population (Bain et al, 1997). The ectopic expression of E2A induces apoptosis of T lymphoma (Engel et al, 2001). Taken together, these data suggest a role of E2A to limit early T cell expansion and promote di erentiation.…”

Section: B Lymphocytesmentioning

confidence: 82%

“…The pro-B cells from EBF +/7 E2A +/7 mice displayed reduced expression of lymphocyte-speci®c genes, including Pax5, Rag1 and Rag2. Di erently, the E2A de®ciency promotes early T lymphocyte expansion (Engel et al, 2001). E2A null mutant mice spontaneously developed monoclonal T lymphoma in thymus between 3 ± 6 months, preceded by a decreased percentage of CD44 low CD25 + cells and increased percentage of CD44 high CD25 7 DN cell population (Bain et al, 1997).…”

Section: B Lymphocytesmentioning

confidence: 99%

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Hematopoietic cytokines, transcription factors and lineage commitment

2002

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The past two decades have witnessed signi®cant advances in our understanding of the cellular physiology and molecular regulation of hematopoiesis. At the heart of stem cell self-renewal and lineage commitment decisions lies the relative expression levels of lineage-speci®c transcription factors. The expression of these transcription factors in early stem cells may be promiscuous and uctuate, but ultimately comes under the in¯uence of extracellular regulatory signals in the form of hematopoietic cytokines. In this review, we ®rst summarize our current understanding of the phenotypic characterization of hematopoietic stem cells. Next, we describe key known transcription factors which govern stem cell selfrenewal and lineage commitment decisions. Finally, we review data concerning the role of speci®c cytokines in in¯uencing these decisions. From this review, a picture emerges in which stem cell fate decisions are governed by the integrated e ects of intrinsic transcription factors and external signaling pathways initiated by regulatory cytokines.

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Section: B Lymphocytesmentioning

confidence: 82%

Section: B Lymphocytesmentioning

confidence: 99%

Hematopoietic cytokines, transcription factors and lineage commitment

2002

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“…Furthermore, they are endowed with a potential tumor-suppressing activity, as inactivation of E2A transcriptional activity is an essential and common step toward the development of T-cell malignancies. Thus, in mice, disruption of the E2A gene or inhibition of E2A proteins by Id proteins leads to abnormalities in the earliest stages of ␣␤ T-cell development and to varying degrees of reduced thymic cellularity (1,11,22,23). Later in life, these E2A-deficient mice become prone to developing highly malignant T-cell lymphomas, most of them expressing either CD4 or CD8.…”

Section: Discussionmentioning

confidence: 99%

Human T-Cell Leukemia Virus Type 1 Tax Protein Down-Regulates Pre-T-Cell Receptor Alpha Gene Transcription in Human Immature Thymocytes

Wencker

Sausse

Derse

et al. 2007

J Virol

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The human pre-T-cell receptor alpha (TCR␣; pT␣) gene encodes a polypeptide which associates with the TCR␤ chain and CD3 molecules to form the pre-TCR complex. The surface expression of the pre-TCR is pT␣ dependent, and signaling through this complex triggers an early ␣␤ T-cell developmental checkpoint inside the thymus, known as ␤-selection. E2A transcription factors, which are involved at multiple stages of T-cell development, regulate the transcription of the pT␣ gene. Here we show that the regulatory protein Tax of the human T-cell leukemia virus type 1 (HTLV-1) efficiently suppresses the E47-mediated activation of the pT␣ promoter. Furthermore, we report that in Tax lentivirally transduced human MOLT-4 T cells, which constitutively express the pT␣ gene, the amount of pT␣ transcripts decreases. Such a decrease is not observed in MOLT-4 cells transduced by a vector encoding the Tax mutant K88A, which is unable to interact with p300. These data underline that Tax inhibits pT␣ transcription by recruiting this coactivator. Finally, we show that the expression of Tax in human immature thymocytes results in a decrease of pT␣ gene transcription but does not modify the level of E47 transcripts. These observations indicate that Tax, by silencing E proteins, down-regulates pT␣ gene transcription during early thymocyte development. They further provide evidence that Tax can interfere with an important checkpoint during T-cell differentiation in the thymus.

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“…The levels of E2A, predominantly expressed as E47, are high in late DN (DN3 and DN4) and early DP T lymphocytes during positive selection of T cells, and low during transition of DP to SP T lymphocytes and in mature T cells (Bain et al, 1999;Engel et al, 2001). It is therefore remarkable that none of the EmMyc T cell lymphomas were of the DN3, DN4 or early DP immature phenotype.…”

Section: Discussionmentioning

confidence: 99%

Proviral activation of the tumor suppressor E2a contributes to T cell lymphomagenesis in EμMyc transgenic mice

2002

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The basic helix -loop -helix factor E2A plays an important role in the development of B and T lymphocytes. In addition, E2a has been implicated as a gene with tumor suppressor activity, since mice deficient for E2a succumb to T cell lymphomas. We have performed retroviral tagging in EmMyc transgenic mice to identify genes that contribute to lymphomagenesis. The EmMyc transgenic mouse is a well-established model of a common translocation in human B cell lymphomas. Analyses of the proviral insertion sites in the MuLVinduced lymphomas revealed that a number of T cell lymphomas carried proviral insertions in the promoter region of E2a. These proviral insertions yield hybrid viral-E2a mRNAs resulting in a marked rise in E2A protein levels. The proviral insertions in E2a were predominantly of clonal origin indicating that E2a insertions are early events in these T cell lymphomas. The primary oncogenic effect of E2A is likely to be associated with enhancement of transcription of the cMyc transgene via binding to the regulatory immunoglobulin enhancers. The results herein thus provide the first evidence that in a specific setting E2A overexpression can contribute to T-lymphomagenesis. This implies that E2a contains oncogenic features in addition to the previously described tumor suppressive properties.

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Early Thymocyte Development Is Regulated by Modulation of E2a Protein Activity

Cited by 168 publications

References 46 publications

Hematopoietic cytokines, transcription factors and lineage commitment

Hematopoietic cytokines, transcription factors and lineage commitment

Human T-Cell Leukemia Virus Type 1 Tax Protein Down-Regulates Pre-T-Cell Receptor Alpha Gene Transcription in Human Immature Thymocytes

Proviral activation of the tumor suppressor E2a contributes to T cell lymphomagenesis in EμMyc transgenic mice

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