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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 Gratzinger, Ramiro Verdun, Nathanael S. Gray and Izidore S. Lossos

Key points

  • GCK signaling is activated in DLBCL, and this signaling is important to DLBCL proliferation and survival.

  • Therapeutic targeting of GCK is feasible and may advance efforts to cure DLBCL patients.

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), yet 40-50% of patients will eventually succumb to their disease demonstrating a pressing need for novel therapeutic options. Gene expression profiling has identified messenger RNA's 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. Since the majority of DLBCL tumors (~80%) exhibit activation of GCK, this therapy may be applicable to most patients.

  • Submitted February 2, 2016.
  • Accepted April 27, 2016.