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dc.contributor.advisorPernis, Alessandra
dc.contributor.authorRicker, Edd
dc.date.accessioned2019-03-26T19:13:04Z
dc.date.available2020-05-08T06:00:40Z
dc.date.issued2018
dc.identifier.urihttps://hdl.handle.net/1813/64783
dc.description.abstractABC-DLBCLs are aggressive B cell malignancies characterized by deregulations in the molecular networks controlling plasma cell (PC) differentiation. The survival of ABC-DLBCLs is known to require the transcription factor IRF4. The mechanisms controlling IRF4 activity in ABC-DLBCLs are not fully understood. ROCK1 and ROCK2 are two serine-threonine kinases that serve as major effector proteins for RhoA, which was recently found to be mutated in several lymphomas. Here we show that IRF4 is constitutively phosphorylated in ABC-DLBCLs. IRF4 phosphorylation is mediated by ROCK2, which is constitutively activated in ABC-DLBCLs, but not in other DLBCLs. ROCK2-mediated IRF4 phosphorylation can be induced by signals that promote PC differentiation and modulates the ability of IRF4 to regulate the expression of a subset of PC genes. Inhibition of ROCK2 in ABC-DLBCLs alters their transcriptional profile not only by controlling IRF4 activity but also by regulating c-MYC protein levels. In addition to ROCK2, ROCK1 also regulates key survival pathways in ABC-DLBCLs and pan-ROCK inhibition decreases the survival of ABC-DLBCLs, but not that of GCB-DLBCLs. We also identified critical roles for ROCK2 in physiological B cell differentiation and showed that lack of ROCK2 in B cells leads to impaired germinal center formation and humoral responses. Together, these findings reveal an important role for ROCK2 in modulating physiological B cell responses upon antigen challenge, delineate the pathophysiological implications of ROCK activation in ABC-DLBCL and other B cell malignancies, and propose that ROCK inhibition could represent a novel therapeutic approach for the treatment of diseases characterized by dysfunctional B cell responses.
dc.language.isoen_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectABC-DLBCL
dc.subjectGerminal Center
dc.subjectIRF4
dc.subjectLymphoma
dc.subjectRhoA
dc.subjectROCK
dc.titleRoles Of The Rho Kinases In B Cell Differentiation And Lymphomagenesis
dc.typedissertation or thesis
thesis.degree.disciplineImmunology & Microbial Pathogenesis
thesis.degree.grantorWeill Cornell Graduate School of Medical Sciences
thesis.degree.levelDoctor of Philosophy


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