Publications

Authors:

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

Title:

Aggressive B-cell Lymphoma with {MYC}/{TP}53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents

Year:

2020

Type of item:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Language:

Inglese

Referee:

No

Name of journal:

MOLECULAR CANCER RESEARCH

ISSN of journal:

1541-7786

N° Volume:

19

Number or Folder:

2

Page numbers:

249-260

Keyword:

Large B-cell lymphoma

Short description of contents:

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.

Product ID:

131153

Handle IRIS:

11562/1082611

Last Modified:

September 22, 2024

Bibliographic citation:

Deng, Manman; Y Xu-Monette, Zijun; V Pham, Lan; Wang, Xudong; Tzankov, Alexandar; Fang, Xiaosheng; Zhu, Feng; Visco, Carlo; Bhagat, Govind; Dybkaer, Karen; Chiu, April; Tam, Wayne; Zu, Youli; Hsi, Eric D.; You, Hua; Huh, Jooryung; Ponzoni, Maurilio; Ferreri, Andres J. M.; B Moller, Michael; M Parsons, Benjamin; Hagemeister, Fredrick; Han van Krieken, J.; A Piris, Miguel; N Winter, Jane; Li, Yong; Xu, Bing; Liu, Phillip; H Young, Ken, Aggressive B-cell Lymphoma with {MYC}/{TP}53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents «MOLECULAR CANCER RESEARCH» , vol. 19 , n. 2 , 2020 , pp. 249-260

Consulta la scheda completa presente nel repository istituzionale della Ricerca di Ateneo