Title | Selective dysregulation of ROCK2 activity promotes aberrant transcriptional networks in ABC diffuse large B-cell lymphoma. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Ricker E, Verma A, Marullo R, Gupta S, Ye C, Pannellini T, Manni M, Tam W, Inghirami G, Elemento O, Cerchietti L, Pernis AB |
Journal | Sci Rep |
Volume | 10 |
Issue | 1 |
Pagination | 13094 |
Date Published | 2020 08 04 |
ISSN | 2045-2322 |
Keywords | Cell 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. |
DOI | 10.1038/s41598-020-69884-1 |
Alternate Journal | Sci Rep |
PubMed ID | 32753663 |
PubMed Central ID | PMC7403583 |
Grant List | R01 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 |