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 Rose Chapman, Elena Cortizas, Ragini Shyam, Shideh Chinichian, Ranjana Advani, Li Tan, Jianming Zhang, Hwan Geun Choi, Robert Tibshirani, Sara J. Buhrlage, Dita GratzingerRamiro Verdun, Nathanael S. Gray, Izidore S. Lossos

Research output: Contribution to journalArticle

5 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Matthews, J. M., Bhatt, S., Patricelli, M. P., Nomanbhoy, T. K., Jiang, X., Natkunam, Y., Gentles, A. J., Martinez, E., Zhu, D., Chapman, J. R., Cortizas, E., Shyam, R., Chinichian, S., Advani, R., Tan, L., Zhang, J., Choi, H. G., Tibshirani, R., Buhrlage, S. J., ... Lossos, I. S. (2016). Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma. Blood, 128(2), 239-248. https://doi.org/10.1182/blood-2016-02-696856