Dal Cin, Paola
Mayo Clinic
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Citations 2
TP63 fusions drive multicomplex enhancer rewiring, lymphomagenesis, and EZH2 dependence
Wu, Gongwei , Yoshida, Noriaki , Liu, Jihe , Xiong, Yuan , Heavican‐Foral, Tayla B. , Mandato, Elisa , Nelson, Geoffrey M. , Yang, Lu , Chen, Renee , Jones, M. , Roshal, Mikhail , Zhang, Yanming , Xu, Ran , Jain, Salvia , Leahy, Catharine, Jones, Kristen L. , Stevenson, Kristen E. , Galasso, Natasha, Ganesan, Nivetha , Chang, Tiffany , Wu, Wenchao, Louissaint, Abner , Debaize, Lydie , Cin, Paola Dal , Chan, Wing C. , Sui, Shannan J. Ho , Ng, Samuel Y., Chen, Chun‐Wei , Weinstock, David M. , Zhang, Xiaoyang , Xiong, Yuan , Nelson, Geoffrey M , Yang, Lu , Donovan, Katherine A , Jones, Marcus K , Zhang, Yanming , Xu, Ran , Nirmal, Ajit J , Jain, Salvia , Ganesan, Nivetha , Chang, Tiffany , Dal Cin, Paola , Ho Sui, Shannan J , Feldman, Andrew L , Horwitz, Steven M , Adelman, Karen , Fischer, Eric S , Chen, Chun-Wei , Weinstock, David M , Brown, Myles , Heavican, Tayla B., Liu, Huiyun , Yoon, Hojong , Feldman, Andrew L. , Horwitz, Steven M. , Brown, Myles
Science Translational Medicine | September 20, 2023 | Volume: 15 | Issue: 714 | Pages: No page available
Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice expressing TBL1XR1::TP63, the most common TP63 fusion, develop diverse lymphomas that recapitulate multiple human T and B cell lymphomas. Here, we identify that TP63 fusions coordinate the recruitment of two epigenetic modifying complexes, the nuclear receptor corepressor (NCoR)—histone deacetylase 3 (HDAC3) by the N-terminal TP63 fusion partner and the lysine methyltransferase 2D (KMT2D) by the C-terminal TP63 component, which are both required for fusion-dependent survival. TBL1XR1::TP63 localization at enhancers drives a unique cell state that involves up-regulation of MYC and the polycomb repressor complex 2 (PRC2) components EED and EZH2. Inhibiting EZH2 with the therapeutic agent valemetostat is highly effective at treating transgenic lymphoma murine models, xenografts, and patient-derived xenografts harboring TP63 fusions. One patient with TP63 -rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.
Guiding the global evolution of cytogenetic testing for hematologic malignancies
Akkari, Yassmine, Baughn, Linda B. , Dubuc, Adrian M. , Smith, Adam C. , Mallo, Mar , Cin, Paola Dal , Díez‐Campelo, María , Gallego, Marta S., Granada, Isabel , Haase, D., Schlegelberger, Brigitte , Slavutsky, Irma , Mecucci, Cristina , Levine, Ross L. , Hasserjian, Robert P. , Solé, Françesc , Levy, Brynn , Xu, Xinjie , Akkari, Yassmine M N , Dal Cin, Paola , Granada Font, Isabel , Baughn, Linda B , Solé, Francesc , Diez-Campelo, Maria , Haase, Detlef
Blood | February 15, 2022 | Volume: 139 | Issue: 15 | Pages: 2273-2284
Abstract Cytogenetics has long represented a critical component in the clinical evaluation of hematologic malignancies. Chromosome banding studies provide a simultaneous snapshot of genome-wide copy number and structural variation, which have been shown to drive tumorigenesis, define diseases, and guide treatment. Technological innovations in sequencing have ushered in our present-day clinical genomics era. With recent publications highlighting novel sequencing technologies as alternatives to conventional cytogenetic approaches, we, an international consortium of laboratory geneticists, pathologists, and oncologists, describe herein the advantages and limitations of both conventional chromosome banding and novel sequencing technologies and share our considerations on crucial next steps to implement these novel technologies in the global clinical setting for a more accurate cytogenetic evaluation, which may provide improved diagnosis and treatment management. Considering the clinical, logistic, technical, and financial implications, we provide points to consider for the global evolution of cytogenetic testing.