TP63 Fusions Drive Enhancer Rewiring, Lymphomagenesis, and Dependence on EZH2

Wu, Gongwei; Yoshida, Noriaki; Liu, Jihe; Zhang, Xiaoyang; Heavican-Foral, Tayla B.; Liu, Huiyun; Nelson, Geoffrey M.; Yang, Lu; Chen, Renee; Jones, M.; Xu, Ran; Nirmal, Ajit J.; Jain, Salvia; Leahy, Catharine; Jones, Kristen L.; Stevenson, Kristen E.; Wu, Wen-Chao; Louissaint, Abner; Debaize, Lydie; Chan, Wing C.; Sui, Shannan Ho; Ng, Samuel Y.; Feldman, Andrew L.; Meyerson, Matthew; Adelman, Karen; Chen, chun-Wei David; Brown, Myles; Weinstock, David M.

doi:10.1182/blood-2022-163368

Cited by 2 publications

(4 citation statements)

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“…Additionally, we discovered an inversion of TBL1XR1 – TP63 in H. pylori -positive cases. The TBL1XR1–TP63 gene fusion has been reported as a recurrent somatic gene fusion in high-grade lymphomas, such as diffuse large B cell lymphoma (DLBCL) and is known to drive tumor survival through EZH2 and upregulate MYC , EZH2 , and EED [40, 45]. Indeed, the sample with the TBL1XR1–TP63 gene fusion in the current study showed high expression of MYC, EZH2, and EED (supplemental Figure 1).…”

Section: Discussionmentioning

confidence: 55%

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Sequencing analysis ofHelicobacter pyloriinfection in gastric mucosa and its progression to gastric mucosa-associated tissue (MALT) lymphoma

Yoo,

Koh,

Byun

et al. 2024

Preprint

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Introduction: The pathogenesis of gastric mucosa-associated tissue (MALT) lymphoma is associated with Helicobacter pylori infection. Although treatment strategies and responsiveness according to the stage of gastric MALT lymphoma have been widely reported, a detailed study of the biological carcinogenic process is still required. Method: Paired, fresh tumor-adjacent normal and gastric mucosal tissue samples from 13 patients with gastric MALT lymphoma were prospectively collected. Whole exome sequencing (WES) and whole-transcriptome sequencing (WTS) data were generated. The analysis of mutations, gene fusion, gene expression, and the microbiome was stratified by H. pylori infection and disease status. Results: Somatic mutations in TRAF3 and TNFAIP3 were identified in H. pylori-negative gastric MALT lymphoma. Fusions involving BIRC3-MALT1 (2 samples) and TBL1XR1-TP63 (1 sample with H. pylori infection) were detected. Stepwise comparative analysis of RNA expression revealed upregulation of immune response, inflammatory responses, and the NF-kappaB signaling pathway in H. pylori-positive MALT lymphoma cases. Pathways associated with pathogens were upregulated in H. pylori-negative MALT lymphoma cases, suggesting that infections other than H. pylori may affect lymphomagenesis. Microbiome analysis revealed that genus_Rothia was negatively correlated with alpha diversity. Conclusion: A stepwise approach using diverse stages of WTS data revealed detailed pathogenic mechanisms of gastric MALT lymphoma. Chronic inflammation following infection contributes to gastric MALT lymphomagenesis in both H. pylori positive and negative cases.

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Section: Discussionmentioning

confidence: 55%

“…We speculate that the TBL1XR1 – TP63 fusion is one of the drivers of the high-grade transformation of gastric MALT lymphoma. Biological studies suggest B-cell lymphoma with TBL1XR1–TP63 gene fusion might be susceptible to EZH1/2 inhibition[45].…”

Section: Discussionmentioning

confidence: 99%

Sequencing analysis ofHelicobacter pyloriinfection in gastric mucosa and its progression to gastric mucosa-associated tissue (MALT) lymphoma

Yoo,

Koh,

Byun

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Ruxolitinib has shown efficacy against T cell lymphomas in clinical trials 5 and has induced remissions in patients with PCM1::JAK2 ‐associated leukaemias 6 . Effective strategies to target TP63 fusions have not been established, but recent data suggest possible sensitivity to EZH2 inhibition 7 . The presence of the TP63 fusion probably contributed to the aggressive disease course in this patient, including resistance to a JAK inhibitor.…”

Section: Figurementioning

confidence: 95%

“…6 Effective strategies to target TP63 fusions have not been established, but recent data suggest possible sensitivity to EZH2 inhibition. 7 The presence of the TP63 fusion probably contributed to the aggressive disease course in this patient, including resistance to a JAK inhibitor. Loss-of-function alterations in CDKN2A and gain-of-function mutations in TERT may also contribute the pathogenesis of PCGDTCL.…”

mentioning

confidence: 91%