Zhang, Yanming
https://orcid.org/0000-0001-6138-6080
Mayo Clinic
Memorial Sloan Kettering Cancer Center
Citations 2
Genomic Features Do Not Account for Differences in Multiple Myeloma Risk by Ancestry
Maclachlan, Kylee , Papadimitriou, Marios , Blaney, Patrick , Baughn, Linda B. , Shekarkhand, Tala , Poos, Alexandra M. , Ziccheddu, Bachisio , Tang, Hongwei , Yan, Huihuang , Diamond, Benjamin , Zhang, Yanming , Cimera, Robert , Hultcrantz, Malin , Mailankody, Sham , Hassoun, Hani , Tan, Carlyn , Brown, Elizabeth , Winterkorn, Lara , Steinsnyder, Zoe , Vaksman, Zalman , Korde, Neha , Weinhold, Niels , Maclachlan, Kylee , Tang, Hongwei , Dogan, Ahmet , Gagler, Dylan , Boyle, Eileen M , Hultcrantz, Malin , Mailankody, Sham , Hassoun, Hani , Shah, Urvi A , Tan, Carlyn R , Brown, Elizabeth E , Winterkorn, Lara , Chu, Timothy , Steinsnyder, Zoe , Vaksman, Zalman , Davies, Faith E , Korde, Neha , Landgren, C Ola , Raab, Marc S , Lesokhin, Alexander M , Robine, Nicolas , Weinhold, Niels , Usmani, Saad , Maura, Francesco , Morgan, Gareth J , Baughn, Linda B , Diamond, Benjamin T , Blaney, Patrick , Poos, Alexandra M. , Doǧan, Ahmet , Boyle, Eileen M. , Shah, Urvi A. , Davies, Faith E. , Landgren, Ola , Raab, Marc S. , Lesokhin, Alexander M. , Usmani, Saad Z. , Maura, Francesco , Morgan, Gareth J.
Blood Cancer Discovery | June 12, 2026 | Volume: No volume available | Issue: No issue available | Pages: OF1-OF17
Abstract Studies have reported conflicting findings regarding the contribution of germline variants or somatic genomic drivers to racial disparities in multiple myeloma. To comprehensively investigate somatic drivers in relation to inherited genetics in multiple myeloma, we combined newly sequenced whole-genome sequencing data with publicly available datasets (total n = 1,286). Overall, we did not identify germline or somatic genomic differences that explain the different risk of developing multiple myeloma between patients with genetic similarity to African (AFR) or European (EUR) reference populations. A difference in the detectability and timing of APOBEC-associated and germinal center mutational activity was observed. Integrating epidemiologic data and mutational signature-based temporal estimates, we challenge the assumption that individuals in the AFR group develop multiple myeloma at a younger age. Finally, we demonstrate that, with equal access to efficacious therapies, patients in the AFR and EUR groups have equivalent clinical outcomes. Significance: Multiple myeloma is reported to occur at higher rates in individuals who self-identify as non-Hispanic Black. In this large dataset, genomic drivers occur at the same rate among ancestry groups, except for APOBEC mutagenesis. With equivalent therapy, clinical outcomes did not differ for patients grouped by genetic ancestry similarity.
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.