Browsing by Author "Aifantis, Iannis"

Now showing 1 - 3 of 3
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    Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion
    (Elsevier, 2023) Battistello, Elena; Hixon, Kimberlee A.; Comstock, Dawn E.; Collings, Clayton K.; Chen, Xufeng; Rodriguez Hernaez, Javier; Lee, Soobeom; Cervantes, Kasey S.; Hinkley, Madeline M.; Ntatsoulis, Konstantinos; Cesarano, Annamaria; Hockemeyer, Kathryn; Haining, W. Nicholas; Witkowski, Matthew T.; Qi, Jun; Tsirigos, Aristotelis; Perna, Fabiana; Aifantis, Iannis; Kadoch, Cigall; Medicine, School of Medicine
    Highly coordinated changes in gene expression underlie T cell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may be targeted for therapeutic benefit remain poorly understood. Here, we comprehensively profile the genomic occupancy of mSWI/SNF chromatin remodeling complexes throughout acute and chronic T cell stimulation, finding that stepwise changes in localization over transcription factor binding sites direct site-specific chromatin accessibility and gene activation leading to distinct phenotypes. Notably, perturbation of mSWI/SNF complexes using genetic and clinically relevant chemical strategies enhances the persistence of T cells with attenuated exhaustion hallmarks and increased memory features in vitro and in vivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control in vivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of T cell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols.
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    Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells
    (SpringerNature, 2017-04-25) Pan, Feng; Wingo, Thomas S.; Zhao, Zhigang; Gao, Rui; Makishima, Hideki; Qu, Guangbo; lin, Li; Yu, Miao; Ortega, Janice R.; Wang, Jiapeng; Nazha, Aziz; Chen, Li; Yao, Bing; Liu, Can; Chen, Shi; Weeks, Ophelia; Ni, Hongyu; Phillips, Brittany Lynn; Huang, Suming; Wang, Jianlong; He, Chuan; Li, Guo-Min; Radivoyevitch, Tomas; Aifantis, Iannis; Maciejewski, Jaroslaw P.; Yang, Feng-Chun; Jin, Peng; Xu, Mingjiang; Department of Pediatrics, School of Medicine
    TET2 is a dioxygenase that catalyses multiple steps of 5-methylcytosine oxidation. Although TET2 mutations frequently occur in various types of haematological malignancies, the mechanism by which they increase risk for these cancers remains poorly understood. Here we show that Tet2-/- mice develop spontaneous myeloid, T- and B-cell malignancies after long latencies. Exome sequencing of Tet2-/- tumours reveals accumulation of numerous mutations, including Apc, Nf1, Flt3, Cbl, Notch1 and Mll2, which are recurrently deleted/mutated in human haematological malignancies. Single-cell-targeted sequencing of wild-type and premalignant Tet2-/- Lin-c-Kit+ cells shows higher mutation frequencies in Tet2-/- cells. We further show that the increased mutational burden is particularly high at genomic sites that gained 5-hydroxymethylcytosine, where TET2 normally binds. Furthermore, TET2-mutated myeloid malignancy patients have significantly more mutational events than patients with wild-type TET2. Thus, Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells, suggesting a novel TET2 loss-mediated mechanism of haematological malignancy pathogenesis.
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    Therapeutic targeting of the E3 ubiquitin ligase SKP2 in T-ALL
    (Springer Nature, 2019-11-26) Rodriguez, Sonia; Abundis, Christina; Boccalatte, Francesco; Mehrotra, Purvi; Chiang, Mark Y.; Yui, Mary A.; Wang, Lin; Zhang, Huajia; Zollman, Amy; Bonfim-Silva, Ricardo; Kloetgen, Andreas; Palmer, Joycelynne; Sandusky, George; Wunderlich, Mark; Kaplan, Mark H.; Mulloy, James C.; Marcucci, Guido; Aifantis, Iannis; Cardoso, Angelo A.; Carlesso, Nadia; Medicine, School of Medicine
    Timed degradation of the cyclin-dependent kinase inhibitor p27Kip1 by the E3 ubiquitin ligase F-box protein SKP2 is critical for T-cell progression into cell cycle, coordinating proliferation and differentiation processes. SKP2 expression is regulated by mitogenic stimuli and by Notch signaling, a key pathway in T-cell development and in T-cell acute lymphoblastic leukemia (T-ALL); however, it is not known whether SKP2 plays a role in the development of T-ALL. Here, we determined that SKP2 function is relevant for T-ALL leukemogenesis, whereas is dispensable for T-cell development. Targeted inhibition of SKP2 by genetic deletion or pharmacological blockade markedly inhibited proliferation of human T-ALL cells in vitro and antagonized disease in vivo in murine and xenograft leukemia models, with little effect on normal tissues. We also demonstrate a novel feed forward feedback loop by which Notch and IL-7 signaling cooperatively converge on SKP2 induction and cell cycle activation. These studies show that the Notch/SKP2/p27Kip1 pathway plays a unique role in T-ALL development and provide a proof-of-concept for the use of SKP2 as a new therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL).