Citations 1
Aggressive B-cell Lymphoma with MYC/TP53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents
Deng, Manman , Pham, Lan V., Wang, Xudong , Tzankov, Alexandar , Zhu, Feng , Visco, Carlo , Bhagat, Govind , Dybkær, Karen , Chiu, April , Tam, Wayne , Zu, Youli , You, Hua , Huh, Jooryung , Ferreri, Andrés J.M. , Møller, Michael , Parsons, Benjamin M. , Hagemeister, Fredrick, Li, Yong , Xu, Bing , Liu, Phillip , Young, Ken H. , Tzankov, Alexandar , Visco, Carlo , Dybkaer, Karen , Ponzoni, Maurilio , Møller, Michael Boe , Parsons, Benjamin M , van Krieken, J Han , Winter, Jane N , Young, Ken H , Li, Yong , Bhagat, Govind , Zu, Youli , Xu‐Monette, Zijun Y. , Fang, Xiaosheng , Hsi, Eric D. , Ponzoni, Maurilio , Krieken, J. Han van , Piris, Miguel Á. , Winter, Jane N.
Molecular Cancer Research | November 5, 2020 | Volume: 19 | Issue: 2 | Pages: 249-260
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, 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 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 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 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/MEK/ERK pathways. In summary, these findings support subclassification of DLBCL/HGBCL with dual MYC/TP53 alterations, which demonstrates distinct pathobiologic 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. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/19/2/249/F1.large.jpg.