Browsing by Author "Sverdlov, M"

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GATA-3 is a proto-oncogene in T-cell lymphoproliferative neoplasms
(Springer Nature, 2022) Geng, X; Wang, C; Gao, X; Chowdhury, P; Weiss, J; Villegas, JA; Saed, B; Perera, T; Hu, Y; Reneau, J; Sverdlov, M; Wolfe, A; Brown, N; Harms, P; Bailey, NG; Inamdar K; Hristov, AC; Tejasvi, T; Montes, J; Barrionuevo, C; Taxa-rojas, L; Casavilca-Sambrano, S; de Pádua Covas Lage JLA; Culler HF; Pereira, J; Runge, JS; Qin, T; Tsoi, LC; Hong, HS; Zhang L; Lyssiotis, CA; Ohe, R; Toubai, T; Zevallos-Morales, A; Murga-Zamalloa, C; Wilcox, RA
Neoplasms originating from thymic T-cell progenitors and post-thymic mature T-cell subsets account for a minority of lymphoproliferative neoplasms. These T-cell derived neoplasms, while molecularly and genetically heterogeneous, exploit transcription factors and signaling pathways that are critically important in normal T-cell biology, including those implicated in antigen-, costimulatory-, and cytokine-receptor signaling. The transcription factor GATA-3 regulates the growth and proliferation of both immature and mature T cells and has recently been implicated in T-cell neoplasms, including the most common mature T-cell lymphoma observed in much of the Western world. Here we show that GATA-3 is a proto-oncogene across the spectrum of T-cell neoplasms, including those derived from T-cell progenitors and their mature progeny, and further define the transcriptional programs that are GATA-3 dependent, which include therapeutically targetable gene products. The discovery that p300-dependent acetylation regulates GATA-3 mediated transcription by attenuating DNA binding has novel therapeutic implications. As most patients afflicted with GATA-3 driven T-cell neoplasms will succumb to their disease within a few years of diagnosis, these findings suggest opportunities to improve outcomes for these patients.
Notch Signaling Promotes Mature T-Cell Lymphomagenesis
(American Association for Cancer Research Inc., 2022) Gao, X; Wang, C; Abdelrahman, S; Kady, N; Murga-Zamalloa, C; Gann, P; Sverdlov, M; Wolfe, A; Polk, A; Brown, N; Bailey, N; Inamdar, K; Casavilca-Zambrano, S; Montes Gil, J; Barrionuevo, C; Taxa-Rojas, L; Reneau, J; Siebe, CW; Maillard, I; Wilcox, RA
Peripheral T-cell lymphomas (PTCL) are agressive lymphomas engineered mouse models and spontaneous PTCL models were that develop from mature T cells. The most common PTCLs are used to functionally examine the role of Notch signaling, and genetically, molecularly, and clinically diverse and are generally Notch1/Notch2 blockade and pan-Notch blockade using domiassociated with dismal outcomes. While Notch signaling plays a nant-negative MAML significantly impaired the proliferation of critically important role in both the development of immature T malignant T cells and PTCL progression in these models. Treatment cells and their malignant transformation, its role in PTCL is poorly with DLL1/DLL4 blocking antibodies established that Notch sigunderstood, despite the increasingly appreciated function of Notch naling is ligand-dependent. Together, these findings reveal a role for in regulating the proliferation and differentiation of mature T cells. ligand-dependent Notch signaling in driving peripheral T-cell Here, we demonstrate that Notch receptors and their Delta-like lymphomagenesis. family ligands (DLL1/DLL4) play a pathogenic role in PTCL. Notch1 activation was observed in common PTCL subtypes, includSignificance: This work demonstrates that ligand-dependent ing PTCL-not otherwise specified (NOS). In a large cohort of PTCL-Notch activation promotes the growth and proliferation of mature NOS biopsies, Notch1 activation was significantly associated with T-cell lymphomas, providing new therapeutic strategies for this surrogate markers of proliferation. Complementary genetically group of aggressive lymphomas. 2022 American Association for Cancer Research.