Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP

Zijun Y. Xu-Monette; Bouthaina S. Dabaja; Xiaoxiao Wang; Meifeng Tu; Ganiraju C. Manyam; Alexander Tzankov; Yi Xia; Li Zhang; Ruifang Sun; Carlo Visco; Karen Dybkaer; Lihui Yin; April Chiu; Attilio Orazi; Youli Zu; Govind Bhagat; Kristy L. Richards; Eric D. Hsi; William W.L. Choi; J. Han Van Krieken; Jooryung Huh; Maurilio Ponzoni; Andrés J.M. Ferreri; Michael B. Møller; Ben M. Parsons; Xiaoying Zhao; Jane N. Winter; Miguel A. Piris; Timothy J. McDonnell; Roberto N. Miranda; Yong Li; L. Jeffrey Medeiros; Ken H. Young

doi:10.1038/modpathol.2015.118

Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP

Zijun Y. Xu-Monette, Bouthaina S. Dabaja, Xiaoxiao Wang, Meifeng Tu, Ganiraju C. Manyam, Alexander Tzankov, Yi Xia, Li Zhang, Ruifang Sun, Carlo Visco, Karen Dybkaer, Lihui Yin, April Chiu, Attilio Orazi, Youli Zu, Govind Bhagat, Kristy L. Richards, Eric D. Hsi, William W.L. Choi, J. Han Van KriekenJooryung Huh, Maurilio Ponzoni, Andrés J.M. Ferreri, Michael B. Møller, Ben M. Parsons, Xiaoying Zhao, Jane N. Winter, Miguel A. Piris, Timothy J. McDonnell, Roberto N. Miranda, Yong Li, L. Jeffrey Medeiros, Ken H. Young^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

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

47 Scopus citations

Abstract

MYC dysregulation, including MYC gene rearrangement and Myc protein overexpression, is of increasing clinical importance in diffuse large B-cell lymphoma (DLBCL). However, the roles of MYC and the relative importance of rearrangement vs overexpression remain to be refined. Gaining knowledge about the tumor biology associated with MYC dysregulation is important to understand the roles of MYC and MYC-associated biology in lymphomagenesis. In this study, we determined MYC rearrangement status (n=344) and Myc expression (n=535) in a well-characterized DLBCL cohort, individually assessed the clinical and pathobiological features of patients with MYC rearrangement and Myc protein overexpression, and analyzed the prognosis and gene expression profiling signatures associated with these MYC abnormalities in germinal center B-cell-like and activated B-cell-like DLBCL. Our results showed that the prognostic importance of MYC rearrangement vs Myc overexpression is significantly different in germinal center B-cell-like vs activated B-cell-like DLBCL. In germinal center B-cell-like DLBCL, MYC-rearranged germinal center B-cell-like DLBCL patients with Myc overexpression significantly contributed to the clinical, biological, and prognostic characteristics of the overall Myc-overexpressing germinal center B-cell-like DLBCL group. In contrast, in activated B-cell-like DLBCL, the occurrence, clinical and biological features, and prognosis of Myc overexpression were independent of MYC rearrangement. High Myc levels and Myc-independent mechanisms, either tumor cell intrinsic or related to tumor microenvironment, conferred significantly worse survival to MYC-rearranged germinal center B-cell-like DLBCL patients, even among Myc high Bcl-2 high DLBCL patients. This study provides new insight into the tumor biology and prognostic effects associated with MYC dysregulation and suggest that detection of both MYC translocations and evaluation of Myc and Bcl-2 expression is necessary to predict the prognosis of DLBCL patients.

Original language	English (US)
Pages (from-to)	1555-1573
Number of pages	19
Journal	Modern Pathology
Volume	28
Issue number	12
DOIs	https://doi.org/10.1038/modpathol.2015.118
State	Published - Dec 1 2015

Funding

This study was supported by the National Cancer Institute/National Institutes of Health (R01CA138688, R01CA187415 and 1RC1CA146299 to YL and KHY). ZYXM is the recipient of the Harold C and Mary L Daily Endowment Fellowships and Shannon Timmins Fellowship for Leukemia Research Award. GM is supported by a grant from the Michael and Susan Dell Foundation. KHY is supported by The University of Texas MD Anderson Cancer Center Lymphoma Moonshot Program, Institutional Research and Development Fund, an Institutional Research Grant Award, an MD Anderson Cancer Center Lymphoma Specialized Programs on Research Excellence (SPORE) Research Development Program Award, an MD Anderson Cancer Center Myeloma SPORE Research Development Program Award, a Gundersen Lutheran Medical Foundation Award, and partially supported by the National Cancer Institute/National Institutes of Health (P50CA136411 and P50CA142509), and by MD Anderson’s Cancer Center Support Grant CA016672.

ASJC Scopus subject areas

General Medicine

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10.1038/modpathol.2015.118

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Xu-Monette, Z. Y., Dabaja, B. S., Wang, X., Tu, M., Manyam, G. C., Tzankov, A., Xia, Y., Zhang, L., Sun, R., Visco, C., Dybkaer, K., Yin, L., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K. L., Hsi, E. D., Choi, W. W. L., ... Young, K. H. (2015). Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP. Modern Pathology, 28(12), 1555-1573. https://doi.org/10.1038/modpathol.2015.118

@article{4e292929b7a64019a45b9d47c3199db2,

title = "Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP",

abstract = "MYC dysregulation, including MYC gene rearrangement and Myc protein overexpression, is of increasing clinical importance in diffuse large B-cell lymphoma (DLBCL). However, the roles of MYC and the relative importance of rearrangement vs overexpression remain to be refined. Gaining knowledge about the tumor biology associated with MYC dysregulation is important to understand the roles of MYC and MYC-associated biology in lymphomagenesis. In this study, we determined MYC rearrangement status (n=344) and Myc expression (n=535) in a well-characterized DLBCL cohort, individually assessed the clinical and pathobiological features of patients with MYC rearrangement and Myc protein overexpression, and analyzed the prognosis and gene expression profiling signatures associated with these MYC abnormalities in germinal center B-cell-like and activated B-cell-like DLBCL. Our results showed that the prognostic importance of MYC rearrangement vs Myc overexpression is significantly different in germinal center B-cell-like vs activated B-cell-like DLBCL. In germinal center B-cell-like DLBCL, MYC-rearranged germinal center B-cell-like DLBCL patients with Myc overexpression significantly contributed to the clinical, biological, and prognostic characteristics of the overall Myc-overexpressing germinal center B-cell-like DLBCL group. In contrast, in activated B-cell-like DLBCL, the occurrence, clinical and biological features, and prognosis of Myc overexpression were independent of MYC rearrangement. High Myc levels and Myc-independent mechanisms, either tumor cell intrinsic or related to tumor microenvironment, conferred significantly worse survival to MYC-rearranged germinal center B-cell-like DLBCL patients, even among Myc high Bcl-2 high DLBCL patients. This study provides new insight into the tumor biology and prognostic effects associated with MYC dysregulation and suggest that detection of both MYC translocations and evaluation of Myc and Bcl-2 expression is necessary to predict the prognosis of DLBCL patients.",

author = "Xu-Monette, {Zijun Y.} and Dabaja, {Bouthaina S.} and Xiaoxiao Wang and Meifeng Tu and Manyam, {Ganiraju C.} and Alexander Tzankov and Yi Xia and Li Zhang and Ruifang Sun and Carlo Visco and Karen Dybkaer and Lihui Yin and April Chiu and Attilio Orazi and Youli Zu and Govind Bhagat and Richards, {Kristy L.} and Hsi, {Eric D.} and Choi, {William W.L.} and {Van Krieken}, {J. Han} and Jooryung Huh and Maurilio Ponzoni and Ferreri, {Andr{\'e}s J.M.} and M{\o}ller, {Michael B.} and Parsons, {Ben M.} and Xiaoying Zhao and Winter, {Jane N.} and Piris, {Miguel A.} and McDonnell, {Timothy J.} and Miranda, {Roberto N.} and Yong Li and Medeiros, {L. Jeffrey} and Young, {Ken H.}",

note = "Publisher Copyright: {\textcopyright} 2015 USCAP, Inc.",

year = "2015",

month = dec,

day = "1",

doi = "10.1038/modpathol.2015.118",

language = "English (US)",

volume = "28",

pages = "1555--1573",

journal = "Modern Pathology",

issn = "0893-3952",

publisher = "Nature Publishing Group",

number = "12",

}

Xu-Monette, ZY, Dabaja, BS, Wang, X, Tu, M, Manyam, GC, Tzankov, A, Xia, Y, Zhang, L, Sun, R, Visco, C, Dybkaer, K, Yin, L, Chiu, A, Orazi, A, Zu, Y, Bhagat, G, Richards, KL, Hsi, ED, Choi, WWL, Van Krieken, JH, Huh, J, Ponzoni, M, Ferreri, AJM, Møller, MB, Parsons, BM, Zhao, X, Winter, JN, Piris, MA, McDonnell, TJ, Miranda, RN, Li, Y, Medeiros, LJ & Young, KH 2015, 'Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP', Modern Pathology, vol. 28, no. 12, pp. 1555-1573. https://doi.org/10.1038/modpathol.2015.118

Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP. / Xu-Monette, Zijun Y.; Dabaja, Bouthaina S.; Wang, Xiaoxiao et al.
In: Modern Pathology, Vol. 28, No. 12, 01.12.2015, p. 1555-1573.

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

TY - JOUR

T1 - Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP

AU - Xu-Monette, Zijun Y.

AU - Dabaja, Bouthaina S.

AU - Wang, Xiaoxiao

AU - Tu, Meifeng

AU - Manyam, Ganiraju C.

AU - Tzankov, Alexander

AU - Xia, Yi

AU - Zhang, Li

AU - Sun, Ruifang

AU - Visco, Carlo

AU - Dybkaer, Karen

AU - Yin, Lihui

AU - Chiu, April

AU - Orazi, Attilio

AU - Zu, Youli

AU - Bhagat, Govind

AU - Richards, Kristy L.

AU - Hsi, Eric D.

AU - Choi, William W.L.

AU - Van Krieken, J. Han

AU - Huh, Jooryung

AU - Ponzoni, Maurilio

AU - Ferreri, Andrés J.M.

AU - Møller, Michael B.

AU - Parsons, Ben M.

AU - Zhao, Xiaoying

AU - Winter, Jane N.

AU - Piris, Miguel A.

AU - McDonnell, Timothy J.

AU - Miranda, Roberto N.

AU - Li, Yong

AU - Medeiros, L. Jeffrey

AU - Young, Ken H.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - MYC dysregulation, including MYC gene rearrangement and Myc protein overexpression, is of increasing clinical importance in diffuse large B-cell lymphoma (DLBCL). However, the roles of MYC and the relative importance of rearrangement vs overexpression remain to be refined. Gaining knowledge about the tumor biology associated with MYC dysregulation is important to understand the roles of MYC and MYC-associated biology in lymphomagenesis. In this study, we determined MYC rearrangement status (n=344) and Myc expression (n=535) in a well-characterized DLBCL cohort, individually assessed the clinical and pathobiological features of patients with MYC rearrangement and Myc protein overexpression, and analyzed the prognosis and gene expression profiling signatures associated with these MYC abnormalities in germinal center B-cell-like and activated B-cell-like DLBCL. Our results showed that the prognostic importance of MYC rearrangement vs Myc overexpression is significantly different in germinal center B-cell-like vs activated B-cell-like DLBCL. In germinal center B-cell-like DLBCL, MYC-rearranged germinal center B-cell-like DLBCL patients with Myc overexpression significantly contributed to the clinical, biological, and prognostic characteristics of the overall Myc-overexpressing germinal center B-cell-like DLBCL group. In contrast, in activated B-cell-like DLBCL, the occurrence, clinical and biological features, and prognosis of Myc overexpression were independent of MYC rearrangement. High Myc levels and Myc-independent mechanisms, either tumor cell intrinsic or related to tumor microenvironment, conferred significantly worse survival to MYC-rearranged germinal center B-cell-like DLBCL patients, even among Myc high Bcl-2 high DLBCL patients. This study provides new insight into the tumor biology and prognostic effects associated with MYC dysregulation and suggest that detection of both MYC translocations and evaluation of Myc and Bcl-2 expression is necessary to predict the prognosis of DLBCL patients.

AB - MYC dysregulation, including MYC gene rearrangement and Myc protein overexpression, is of increasing clinical importance in diffuse large B-cell lymphoma (DLBCL). However, the roles of MYC and the relative importance of rearrangement vs overexpression remain to be refined. Gaining knowledge about the tumor biology associated with MYC dysregulation is important to understand the roles of MYC and MYC-associated biology in lymphomagenesis. In this study, we determined MYC rearrangement status (n=344) and Myc expression (n=535) in a well-characterized DLBCL cohort, individually assessed the clinical and pathobiological features of patients with MYC rearrangement and Myc protein overexpression, and analyzed the prognosis and gene expression profiling signatures associated with these MYC abnormalities in germinal center B-cell-like and activated B-cell-like DLBCL. Our results showed that the prognostic importance of MYC rearrangement vs Myc overexpression is significantly different in germinal center B-cell-like vs activated B-cell-like DLBCL. In germinal center B-cell-like DLBCL, MYC-rearranged germinal center B-cell-like DLBCL patients with Myc overexpression significantly contributed to the clinical, biological, and prognostic characteristics of the overall Myc-overexpressing germinal center B-cell-like DLBCL group. In contrast, in activated B-cell-like DLBCL, the occurrence, clinical and biological features, and prognosis of Myc overexpression were independent of MYC rearrangement. High Myc levels and Myc-independent mechanisms, either tumor cell intrinsic or related to tumor microenvironment, conferred significantly worse survival to MYC-rearranged germinal center B-cell-like DLBCL patients, even among Myc high Bcl-2 high DLBCL patients. This study provides new insight into the tumor biology and prognostic effects associated with MYC dysregulation and suggest that detection of both MYC translocations and evaluation of Myc and Bcl-2 expression is necessary to predict the prognosis of DLBCL patients.

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ER -

Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP

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