eCommons

 

Roles Of The Rho Kinases In B Cell Differentiation And Lymphomagenesis

Other Titles

Author(s)

Abstract

ABC-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.

Journal / Series

Volume & Issue

Description

Sponsorship

Date Issued

2018

Publisher

Keywords

ABC-DLBCL; Germinal Center; IRF4; Lymphoma; RhoA; ROCK

Location

Effective Date

Expiration Date

Sector

Employer

Union

Union Local

NAICS

Number of Workers

Committee Chair

Committee Co-Chair

Committee Member

Degree Discipline

Immunology & Microbial Pathogenesis

Degree Name

Degree Level

Doctor of Philosophy

Related Version

Related DOI

Related To

Related Part

Based on Related Item

Has Other Format(s)

Part of Related Item

Related To

Related Publication(s)

Link(s) to Related Publication(s)

References

Link(s) to Reference(s)

Previously Published As

Government Document

ISBN

ISMN

ISSN

Other Identifiers

Rights

Attribution-NonCommercial-NoDerivatives 4.0 International

Types

dissertation or thesis

Accessibility Feature

Accessibility Hazard

Accessibility Summary

Link(s) to Catalog Record