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. Møller; Benjamin M. Parsons; Fredrick Hagemeister; J. Han van Krieken; Miguel A. Piris; Jane N. Winter; Yong Li; Bing Xu; Phillip Liu; Ken H. Young

doi:10.1158/1541-7786.MCR-20-0466

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. Møller, Benjamin M. ParsonsFredrick Hagemeister, J. Han van Krieken, Miguel A. Piris, Jane N. Winter, Yong Li, Bing Xu, Phillip Liu^*, Ken H. Young^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

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.

Original language	English (US)
Pages (from-to)	249-260
Number of pages	12
Journal	Molecular Cancer Research
Volume	19
Issue number	2
DOIs	https://doi.org/10.1158/1541-7786.MCR-20-0466
State	Published - Feb 1 2021

Funding

G. Bhagat reports personal fees from Seattle Genetics and Boston Biomedical Inc. outside the submitted work. E.D. Hsi reports other from Eli Lilly and Abbvie, personal fees from Seattle Genetics, Jazz Pharmaceuticals, and Miltenyi Biotec outside the submitted work. B.M. Parsons reports personal fees from Bristol-Myers Squibb, Amgen, and AstraZeneca outside the submitted work. M.A. Piris reports grants from Spanish Association Against Cancer (AECC) during the conduct of the study, grants and personal fees from Takeda, grants from Gilead, and personal fees from EUSA outside the submitted work. J.N. Winter reports grants and personal fees from Merck, Karyopharm, AstraZeneca, Bayer, and Adicet Bio, and grants from Glaxo-Smith-Kline outside the submitted work. No disclosures were reported by the other authors. This work was supported by NCI/NIH grants 1R01CA233490-01A1, R01CA138688, R01CA187415, and 1RC1CA146299 to K.H. Young and Y. Li. K.H. Young is also supported by The Duke University Institutional Research Grant Award, Hagemeister Lymphoma Foundation, and Incyte Pharmaceutical Corporation.

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General Medicine

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10.1158/1541-7786.MCR-20-0466

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Deng, M., Xu-Monette, Z. Y., Pham, L. V., Wang, X., Tzankov, A., Fang, X., Zhu, F., Visco, C., Bhagat, G., Dybkaer, K., Chiu, A., Tam, W., Zu, Y., Hsi, E. D., You, H., Huh, J., Ponzoni, M., Ferreri, A. J. M., Møller, M. B., ... Young, K. H. (2021). Aggressive B-cell lymphoma with MYC/TP53 dual alterations displays distinct clinicopathobiological features and response to novel targeted agents. Molecular Cancer Research, 19(2), 249-260. https://doi.org/10.1158/1541-7786.MCR-20-0466

@article{e3698ad4763145058944ab3d81728867,

title = "Aggressive B-cell lymphoma with MYC/TP53 dual alterations displays distinct clinicopathobiological features and response to novel targeted agents",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",

year = "2021",

month = feb,

day = "1",

doi = "10.1158/1541-7786.MCR-20-0466",

language = "English (US)",

volume = "19",

pages = "249--260",

journal = "Molecular Cancer Research",

issn = "1541-7786",

publisher = "American Association for Cancer Research Inc.",

number = "2",

}

Deng, 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, van Krieken, JH, Piris, MA, Winter, JN, Li, Y, Xu, B, Liu, P & Young, KH 2021, 'Aggressive B-cell lymphoma with MYC/TP53 dual alterations displays distinct clinicopathobiological features and response to novel targeted agents', Molecular Cancer Research, vol. 19, no. 2, pp. 249-260. https://doi.org/10.1158/1541-7786.MCR-20-0466

TY - JOUR

T1 - Aggressive B-cell lymphoma with MYC/TP53 dual alterations displays distinct clinicopathobiological features and response to novel targeted agents

AU - Deng, Manman

AU - Xu-Monette, Zijun Y.

AU - Pham, Lan V.

AU - Wang, Xudong

AU - Tzankov, Alexandar

AU - Fang, Xiaosheng

AU - Zhu, Feng

AU - Visco, Carlo

AU - Bhagat, Govind

AU - Dybkaer, Karen

AU - Chiu, April

AU - Tam, Wayne

AU - Zu, Youli

AU - Hsi, Eric D.

AU - You, Hua

AU - Huh, Jooryung

AU - Ponzoni, Maurilio

AU - Ferreri, Andres J.M.

AU - Møller, Michael B.

AU - Parsons, Benjamin M.

AU - Hagemeister, Fredrick

AU - van Krieken, J. Han

AU - Piris, Miguel A.

AU - Winter, Jane N.

AU - Li, Yong

AU - Xu, Bing

AU - Liu, Phillip

AU - Young, Ken H.

PY - 2021/2/1

Y1 - 2021/2/1

N2 - 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.

AB - 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.

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U2 - 10.1158/1541-7786.MCR-20-0466

DO - 10.1158/1541-7786.MCR-20-0466

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SN - 1541-7786

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JF - Molecular Cancer Research

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Aggressive B-cell lymphoma with MYC/TP53 dual alterations displays distinct clinicopathobiological features and response to novel targeted agents

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