Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma

Julie Marie Matthews, Shruti Bhatt, Matthew P. Patricelli, Tyzoon K. Nomanbhoy, Xiaoyu Jiang, Yasodha Natkunam, Andrew J. Gentles, Ezequiel Martinez, Daxing Zhu, Jennifer Chapman-Fredricks, Elena Cortizas, Ragini Shyam, Shideh Chinichian, Ranjana Advani, Li Tan, Jianming Zhang, Hwan Geun Choi, Robert Tibshirani, Sara J. Buhrlage, Dita GratzingerRamiro E Verdun, Nathanael S. Gray, Izidore Lossos

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, yet 40% to 50% of patients will eventually succumb to their disease, demonstrating a pressing need for novel therapeutic options. Gene expression profiling has identified messenger RNAs that lead to transformation, but critical events transforming cells are normally executed by kinases. Therefore, we hypothesized that previously unrecognized kinases may contribute to DLBCL pathogenesis. We performed the first comprehensive analysis of global kinase activity in DLBCL, to identify novel therapeutic targets, and discovered that germinal center kinase (GCK) was extensively activated. GCK RNA interference and small molecule inhibition induced cell-cycle arrest and apoptosis in DLBCL cell lines and primary tumors in vitro and decreased the tumor growth rate in vivo, resulting in a significantly extended lifespan of mice bearing DLBCL xenografts. GCK expression was also linked to adverse clinical outcome in a cohort of 151 primary DLBCL patients. These studies demonstrate, for the first time, that GCK is a molecular therapeutic target in DLBCL tumors and that inhibiting GCK may significantly extend DLBCL patient survival. Because the majority of DLBCL tumors (∼80%) exhibit activation of GCK, this therapy may be applicable to most patients.

Original languageEnglish (US)
Pages (from-to)239-248
Number of pages10
JournalBlood
Volume128
Issue number2
DOIs
StatePublished - Jul 14 2016

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Lymphoma, Large B-Cell, Diffuse
Cells
Tumors
Phosphotransferases
Bearings (structural)
Therapeutics
Heterografts
Gene expression
germinal center kinases
Neoplasms
Chemical activation
Gene Expression Profiling
RNA
Apoptosis
RNA Interference
Cell Cycle Checkpoints
Tumor Cell Line
Non-Hodgkin's Lymphoma
Messenger RNA
Molecules

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma. / Matthews, Julie Marie; Bhatt, Shruti; Patricelli, Matthew P.; Nomanbhoy, Tyzoon K.; Jiang, Xiaoyu; Natkunam, Yasodha; Gentles, Andrew J.; Martinez, Ezequiel; Zhu, Daxing; Chapman-Fredricks, Jennifer; Cortizas, Elena; Shyam, Ragini; Chinichian, Shideh; Advani, Ranjana; Tan, Li; Zhang, Jianming; Choi, Hwan Geun; Tibshirani, Robert; Buhrlage, Sara J.; Gratzinger, Dita; Verdun, Ramiro E; Gray, Nathanael S.; Lossos, Izidore.

In: Blood, Vol. 128, No. 2, 14.07.2016, p. 239-248.

Research output: Contribution to journalArticle

Matthews, JM, Bhatt, S, Patricelli, MP, Nomanbhoy, TK, Jiang, X, Natkunam, Y, Gentles, AJ, Martinez, E, Zhu, D, Chapman-Fredricks, J, Cortizas, E, Shyam, R, Chinichian, S, Advani, R, Tan, L, Zhang, J, Choi, HG, Tibshirani, R, Buhrlage, SJ, Gratzinger, D, Verdun, RE, Gray, NS & Lossos, I 2016, 'Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma', Blood, vol. 128, no. 2, pp. 239-248. https://doi.org/10.1182/blood-2016-02-696856
Matthews, Julie Marie ; Bhatt, Shruti ; Patricelli, Matthew P. ; Nomanbhoy, Tyzoon K. ; Jiang, Xiaoyu ; Natkunam, Yasodha ; Gentles, Andrew J. ; Martinez, Ezequiel ; Zhu, Daxing ; Chapman-Fredricks, Jennifer ; Cortizas, Elena ; Shyam, Ragini ; Chinichian, Shideh ; Advani, Ranjana ; Tan, Li ; Zhang, Jianming ; Choi, Hwan Geun ; Tibshirani, Robert ; Buhrlage, Sara J. ; Gratzinger, Dita ; Verdun, Ramiro E ; Gray, Nathanael S. ; Lossos, Izidore. / Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma. In: Blood. 2016 ; Vol. 128, No. 2. pp. 239-248.
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AU - Nomanbhoy, Tyzoon K.

AU - Jiang, Xiaoyu

AU - Natkunam, Yasodha

AU - Gentles, Andrew J.

AU - Martinez, Ezequiel

AU - Zhu, Daxing

AU - Chapman-Fredricks, Jennifer

AU - Cortizas, Elena

AU - Shyam, Ragini

AU - Chinichian, Shideh

AU - Advani, Ranjana

AU - Tan, Li

AU - Zhang, Jianming

AU - Choi, Hwan Geun

AU - Tibshirani, Robert

AU - Buhrlage, Sara J.

AU - Gratzinger, Dita

AU - Verdun, Ramiro E

AU - Gray, Nathanael S.

AU - Lossos, Izidore

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N2 - Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, yet 40% to 50% of patients will eventually succumb to their disease, demonstrating a pressing need for novel therapeutic options. Gene expression profiling has identified messenger RNAs that lead to transformation, but critical events transforming cells are normally executed by kinases. Therefore, we hypothesized that previously unrecognized kinases may contribute to DLBCL pathogenesis. We performed the first comprehensive analysis of global kinase activity in DLBCL, to identify novel therapeutic targets, and discovered that germinal center kinase (GCK) was extensively activated. GCK RNA interference and small molecule inhibition induced cell-cycle arrest and apoptosis in DLBCL cell lines and primary tumors in vitro and decreased the tumor growth rate in vivo, resulting in a significantly extended lifespan of mice bearing DLBCL xenografts. GCK expression was also linked to adverse clinical outcome in a cohort of 151 primary DLBCL patients. These studies demonstrate, for the first time, that GCK is a molecular therapeutic target in DLBCL tumors and that inhibiting GCK may significantly extend DLBCL patient survival. Because the majority of DLBCL tumors (∼80%) exhibit activation of GCK, this therapy may be applicable to most patients.

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