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 V Pham, 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

24 Citationer (Scopus)

Abstract

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, DLBCL patients 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 MYC/TP53/BCL-2 targeted agents were investigated in DLBCL 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 INCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced cytotoxicity 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 INCB057643, DS3032b and venetoclax to induce cell cycle arrest and apoptosis and to inhibit AKT/MEK/ERK/mTOR pathways, as well as potential drug-resistance mechanisms mediated by upregulation of MCL-1 and RAS/RAF/mTOR pathways. In summary, these findings support sub-classification of DLBCL/HGBCL with dual MYC/TP53 alterations which demonstrates distinct pathobiological features and dismal survival with standard therapy therefore requiring additional targeted therapies. Implications: The clinical and pharmacologic studies suggest recognizing DLBCL with concomitant TP53 mutation and MYC abnormalities as a distinctive entity necessary for precision oncology practice.

OriginalsprogEngelsk
TidsskriftMolecular Cancer Research
Vol/bind19
Udgave nummer2
Sider (fra-til)249-260
Antal sider12
ISSN1541-7786
DOI
StatusUdgivet - 1 feb. 2021

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