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Open Access 01-12-2024 | Mantle Cell Lymphoma | Research

The HSP90-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma

Authors: Fangfang Yan, Vivian Jiang, Alexa Jordan, Yuxuan Che, Yang Liu, Qingsong Cai, Yu Xue, Yijing Li, Joseph McIntosh, Zhihong Chen, Jovanny Vargas, Lei Nie, Yixin Yao, Heng-Huan Lee, Wei Wang, JohnNelson R. Bigcal, Maria Badillo, Jitendra Meena, Christopher Flowers, Jia Zhou, Zhongming Zhao, Lukas M. Simon, Michael Wang

Published in: Experimental Hematology & Oncology | Issue 1/2024

Abstract

Brexucabtagene autoleucel CAR-T therapy is highly efficacious in overcoming resistance to Bruton’s tyrosine kinase inhibitors (BTKi) in mantle cell lymphoma. However, many patients relapse post CAR-T therapy with dismal outcomes. To dissect the underlying mechanisms of sequential resistance to BTKi and CAR-T therapy, we performed single-cell RNA sequencing analysis for 66 samples from 25 patients treated with BTKi and/or CAR-T therapy and conducted in-depth bioinformatics™ analysis. Our analysis revealed that MYC activity progressively increased with sequential resistance. HSP90AB1 (Heat shock protein 90 alpha family class B member 1), a MYC target, was identified as early driver of CAR-T resistance. CDK9 (Cyclin-dependent kinase 9), another MYC target, was significantly upregulated in Dual-R samples. Both HSP90AB1 and CDK9 expression were correlated with MYC activity levels. Pharmaceutical co-targeting of HSP90 and CDK9 synergistically diminished MYC activity, leading to potent anti-MCL activity. Collectively, our study revealed that HSP90-MYC-CDK9 network is the primary driving force of therapeutic resistance.

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Title: The HSP90-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma
Authors: Fangfang Yan
Vivian Jiang
Alexa Jordan
Yuxuan Che
Yang Liu
Qingsong Cai
Yu Xue
Yijing Li
Joseph McIntosh
Zhihong Chen
Jovanny Vargas
Lei Nie
Yixin Yao
Heng-Huan Lee
Wei Wang
JohnNelson R. Bigcal
Maria Badillo
Jitendra Meena
Christopher Flowers
Jia Zhou
Zhongming Zhao
Lukas M. Simon
Michael Wang
Publication date: 01-12-2024
Publisher: BioMed Central
Keyword: Mantle Cell Lymphoma
Published in: Experimental Hematology & Oncology / Issue 1/2024
Electronic ISSN: 2162-3619
DOI: https://doi.org/10.1186/s40164-024-00484-9

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