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

TitleAggressive B-cell Lymphoma with MYC/TP53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents.
Publication TypeJournal Article
Year of Publication2021
AuthorsDeng M, Xu-Monette ZY, Pham LV, Wang X, Tzankov A, Fang X, Zhu F, Visco C, Bhagat G, Dybkaer K, Chiu A, Tam W, Zu Y, Hsi ED, You H, Huh J, Ponzoni M, Ferreri AJM, Møller MB, Parsons BM, Hagemeister F, J van Krieken H, Piris MA, Winter JN, Li Y, Xu B, Liu P, Young KH
JournalMol Cancer Res
Volume19
Issue2
Pagination249-260
Date Published2021 02
ISSN1557-3125
Abstract

Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with / double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether mutation synergizes with MYC abnormalities ( 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-/-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of // status. Combining INCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced the cytotoxic effects in HGBCL-DH without mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent 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 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.

DOI10.1158/1541-7786.MCR-20-0466
Alternate JournalMol Cancer Res
PubMed ID33154093
PubMed Central IDPMC8092941
Grant ListR01 CA138688 / CA / NCI NIH HHS / United States
R01 CA187415 / CA / NCI NIH HHS / United States
R01 CA233490 / CA / NCI NIH HHS / United States
RC1 CA146299 / CA / NCI NIH HHS / United States
Related Faculty: 
Wayne Tam, M.D., Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
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