The Ectopic Expression of Meiosis Regulatory Genes in Cutaneous T-Cell Lymphomas (CTCL)

Increasing evidence supports a potential role for STAT3 as a tumor driver in cutaneous T-cell lymphomas (CTCL). The mechanisms leading to STAT3 activation are not fully understood; however, we recently found that miR-124, a known STAT3 regulator, is robustly silenced in MF tumor-stage and CTCL cells. Objective: We studied here whether deregulation of miR-124 contributes to STAT3 pathway activation in CTCL. Methods: We measured the effect of ectopic mir-124 expression in active phosphorylated STAT3 (p-STAT3) levels and evaluated the transcriptional impact of miR-124-dependent STAT3 pathway regulation by expression microarray analysis. Results: We found that ectopic expression of miR-124 results in massive downregulation of activated STAT3 in different CTCL lines, which resulted in a significant alteration of genetic signatures related with gene transcription and proliferation such as MYC and E2F. Conclusions: Our study highlights the importance of the miR-124/STAT3 axis in CTCL and demonstrates that the STAT3 pathway is regulated through epigenetic mechanisms in these cells. Since deregulated STAT3 signaling has a major impact on CTCL initiation and progression, a better understanding of the molecular basis of the miR-124/STAT3 axis may provide useful information for future personalized therapies.

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Notch1 co-opts lymphoid enhancer factor 1 for survival of murine T-cell lymphomas

Blood ◽

10.1182/blood-2007-04-084202 ◽

2007 ◽

Vol 110 (7) ◽

pp. 2650-2658 ◽

Cited By ~ 30

Author(s):

Christina Spaulding ◽

Erica J. Reschly ◽

Derek E. Zagort ◽

Yumi Yashiro-Ohtani ◽

Levi J. Beverly ◽

...

Keyword(s):

Transcription Factor ◽

T Cell ◽

Cell Lymphoma ◽

Ectopic Expression ◽

Malignant Cell ◽

T Cell Lymphomas ◽

Notch1 Mutations ◽

Enhancer Factor

Oncogenic Notch1 mutations are found in most T-lineage acute lymphoblastic leukemias in humans and T-cell lymphomas in mice. However, the mechanism by which Notch1 promotes transformation or maintains malignant cell survival has not been determined fully. Here, we report that expression of the transcription factor lymphoid enhancer factor 1 (Lef1) is Notch dependent in murine T-cell lymphomas in vitro and in vivo, and that the intracellular domain of Notch1 (ICN1) is present at the Lef1 promoter. Lef1 expression is not Notch dependent in primary T-cell progenitors, but Lef1 mRNA is increased by ectopic expression of ICN1 in these cells. We show that Lef1 is required for survival of T-cell lymphoma lines, and that ectopic expression of Lef1 delays lymphoma cell death in the absence of Notch signaling, indicating that Lef1 is an important Notch target in these cells. Therefore, Notch1 co-opts Lef1 during the process of transformation to maintain survival of T-cell lymphomas.

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Notch1 promotes survival of E2A-deficient T cell lymphomas through pre–T cell receptor–dependent and –independent mechanisms

Blood ◽

10.1182/blood-2005-09-3551 ◽

2006 ◽

Vol 107 (10) ◽

pp. 4115-4121 ◽

Cited By ~ 35

Author(s):

Erica J. Reschly ◽

Christina Spaulding ◽

Tomas Vilimas ◽

W. Vallen Graham ◽

Rachel L. Brumbaugh ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Ectopic Expression ◽

Cell Receptor ◽

Transcription Factor Activity ◽

Factor Activity ◽

Second Hit ◽

Intracellular Form ◽

T Cell Lymphomas ◽

Dependent Mechanism

Loss of E2A transcription factor activity or activation of the intracellular form of Notch1 (ICN) leads to the development of leukemia or lymphoma in humans or mice, respectively. Current models propose that ICN functions by suppressing E2A through a pre–T cell receptor (TCR)–dependent mechanism. Here we show that lymphomas arising in E2A–/– mice require the activation of Notch1 for their survival and have accumulated mutations in, or near, the Notch1 PEST domain, resulting in increased stability and signaling. In contrast, lymphomas arising in p53–/– mice show the activation of Notch1, but no mutations were identified in ICN. The requirement for Notch1 signaling in E2A–/– lymphomas cannot be overcome by ectopic expression of pTα; however, pTα is required for optimal survival and expansion of these cells. Our findings indicate that the activation of Notch1 is an important “second hit” for the transformation of E2A–/– T cell lymphomas and that Notch1 promotes survival through pre–TCR-dependent and -independent mechanisms.

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100 Does ectopic expression of germ cell proteins contribute to genomic instability in cutaneous T-cell lymphomas?

Journal of Investigative Dermatology ◽

10.1016/j.jid.2017.02.114 ◽

2017 ◽

Vol 137 (5) ◽

pp. S17

Author(s):

M. Tsang ◽

J. Gantchev ◽

I. Litvinov

Keyword(s):

T Cell ◽

Germ Cell ◽

Genomic Instability ◽

Ectopic Expression ◽

T Cell Lymphomas

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167 Ectopic expression of meiosis proteins and the LINE-1 retrotransposon is associated with genomic instability in cutaneous T-Cell lymphomas

Journal of Investigative Dermatology ◽

10.1016/j.jid.2018.03.172 ◽

2018 ◽

Vol 138 (5) ◽

pp. S28

Author(s):

M. Tsang ◽

J. Gantchev ◽

D. Sasseville ◽

I. Litvinov

Keyword(s):

T Cell ◽

Genomic Instability ◽

Ectopic Expression ◽

T Cell Lymphomas

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Oncogenic role of Pax5 in the T-lymphoid lineage upon ectopic expression from the immunoglobulin heavy-chain locus

Blood ◽

10.1182/blood-2006-03-009670 ◽

2006 ◽

Vol 109 (1) ◽

pp. 281-289 ◽

Cited By ~ 37

Author(s):

Abdallah Souabni ◽

Wolfram Jochum ◽

Meinrad Busslinger

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Heavy Chain ◽

Ectopic Expression ◽

Immunoglobulin Heavy Chain ◽

Lymphoid Lineage ◽

Igh Locus ◽

T Cell Lymphomas ◽

Cell Gene Expression

Abstract Four of 9 PAX transcription factor genes have been associated with chromosomal translocations in human tumors, although their oncogenic potential has not yet been demonstrated in transgenic mouse models. The B-lymphoidPAX5 gene participates in the generation of the t(9;14)(p13;q32) translocation in germinal center B cells, which leads to deregulated PAX5 expression under the control of the immunoglobulin heavy-chain (IgH) locus in a subset of B-cell non-Hodgkin lymphomas. Here we reconstructed a human t(9;14) translocation in a knock-in mouse by inserting a PAX5 minigene into the IgH locus. The IgHP5ki allele, which corresponds to a germline rather than somatic mutation, is activated in multipotent hematopoietic progenitors and is subsequently expressed in dendritic cells (DCs) and in natural killer (NK), T, and B cells. Ectopic Pax5 expression interferes with normal T-cell development and causes immature T-lymphoblastic lymphomas in IgHP5ki/+ and IgHP5ki/P5ki mice. Aggressive T-cell lymphomas develop even faster in IkPax5/+ mice expressing Pax5 from the Ikaros locus. Pax5 expression in thymocytes activates B-cell–specific genes and represses T-lymphoid genes, suggesting that Pax5 contributes to lymphomagenesis by deregulating the T-cell gene-expression program. These data identify Pax5 as a potent oncogene and demonstrate that the T-lymphoid lineage is particularly sensitive to the oncogenic action of Pax5.

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