Selective dysregulation of ROCK2 activity promotes aberrant transcriptional networks in ABC diffuse large B-cell lymphoma.

TitleSelective dysregulation of ROCK2 activity promotes aberrant transcriptional networks in ABC diffuse large B-cell lymphoma.
Publication TypeJournal Article
Year of Publication2020
AuthorsRicker E, Verma A, Marullo R, Gupta S, Ye C, Pannellini T, Manni M, Tam W, Inghirami G, Elemento O, Cerchietti L, Pernis AB
JournalSci Rep
Volume10
Issue1
Pagination13094
Date Published2020 08 04
ISSN2045-2322
KeywordsCell Line, Tumor, Gene Regulatory Networks, Humans, Interferon Regulatory Factors, Lymphoma, Large B-Cell, Diffuse, Phosphorylation, Proto-Oncogene Proteins c-myc, rho-Associated Kinases, Transcription, Genetic
Abstract

Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive subtype of lymphoma usually associated with inferior outcomes. ABC-DLBCL exhibits plasmablastic features and is characterized by aberrancies in the molecular networks controlled by IRF4. The signaling pathways that are dysregulated in ABC-DLBCL are, however, not fully understood. ROCK2 is a serine-threonine kinase whose role in lymphomagenesis is unknown. Here we show that ROCK2 activity is constitutively dysregulated in ABC-DLBCL but not in GCB-DLBCL and BL. We furthermore show that ROCK2 phosphorylates IRF4 and that the ROCK2-mediated phosphorylation of IRF4 modulates its ability to regulate a subset of target genes. In addition to its effects on IRF4, ROCK2 also controls the expression of MYC in ABC-DLBCL by regulating MYC protein levels. ROCK inhibition furthermore selectively decreases the proliferation and survival of ABC-DLBCL in vitro and inhibits ABC-DLBCL growth in xenograft models. Thus, dysregulated ROCK2 activity contributes to the aberrant molecular program of ABC-DLBCL via its dual ability to modulate both IRF4- and MYC-controlled gene networks and ROCK inhibition could represent an attractive therapeutic target for the treatment of ABC-DLBCL.

DOI10.1038/s41598-020-69884-1
Alternate JournalSci Rep
PubMed ID32753663
PubMed Central IDPMC7403583
Grant ListR01 AR070146 / AR / NIAMS NIH HHS / United States
R01 CA194547 / CA / NCI NIH HHS / United States
F31 CA196209 / CA / NCI NIH HHS / United States
U24 CA210989 / CA / NCI NIH HHS / United States
S10 OD019986 / OD / NIH HHS / United States
P50 CA211024 / CA / NCI NIH HHS / United States
R01 AR064883 / AR / NIAMS NIH HHS / United States