Aggressive B-cell Lymphoma with MYC/TP53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents

Manman Deng, Zijun Y. Xu-Monette, Lan Pham V, Xudong Wang, Alexandar Tzankov, Xiaosheng Fang, Feng Zhu, Carlo Visco, Govind Bhagat, Karen Dybkaer, April Chiu, Wayne Tam, Youli Zu, Eric D. Hsi, Hua You, Jooryung Huh, Maurilio Ponzoni, Andres J. M. Ferreri, Michael B. Moller, Benjamin M. ParsonsFredrick Hagemeister, J. Han van Krieken, Miguel A. Piris, Jane N. Winter, Yong Li, Bing Xu, Phillip Liu, Ken H. Young

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Abstrakt

Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with MYC/BCL2 double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether TP53 mutation synergizes with MYC abnormalities (MYC rearrangement and/or Myc protein overexpression) contributing to HGBCL-like biology and prognosis is not well investigated. In this study, patients with DLBCL with MYC/TP53 abnormalities demonstrated poor clinical outcome, high-grade morphology, and distinct gene expression signatures. To identify more effective therapies for this distinctive DLBCL subset, novel MYOTP53/BCI.-2-targeted agents were investigated in DLBCI. cells with MYC/TP53 dual alterations or HGBCL-MYC/BCL2-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of MYC/BCL2/TP53 status. Combining LNCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced the cytotoxic effects in HGBCL-DH without TP53 mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent TP53 mutation. Reverse-phase protein arrays revealed the synergistic molecular actions by INICB057643, DS3032b and venetoclax to induce cellcycle arrest and apoptosis and to inhibit A KT/MEK/ERK/mTOR pathways, as well as potential drug resistance mechanisms mediated by upregulation of Mcl-1 and RAS/RAF/MEK/ERK pathways. In summary, these findings support subclassification of DLBCL/HGBCL with dual MYC/1153 alterations, which demonstrates distinct pathobiologic features and dismal survival with standard therapy, therefore requiring additional targeted therapies.
OriginalsprogEngelsk
TidsskriftMolecular Cancer Research
Vol/bind19
Udgave nummer2
Sider (fra-til)249-260
ISSN1541-7786
DOI
StatusUdgivet - feb. 2021

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