Expression of the prosurvival kinase HCK requires PAX5 and mutated MYD88 signaling in MYD88-driven B-cell lymphomas
| Autor: | Maria Luisa Guerrera, Xia Liu, Nickolas Tsakmaklis, Andrew Keezer, Jiaji G. Chen, Cristina Jimenez, Kirsten Meid, Christopher J. Patterson, Guang Yang, Manit Munshi, Maria Demos, Amanda Kofides, Lian Xu, Steven P. Treon, Jorge J. Castillo, Gloria Chan, Zachary R. Hunter |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
JUNB 03 medical and health sciences 0302 clinical medicine Transcription (biology) hemic and lymphatic diseases Transcriptional regulation Humans STAT3 Transcription factor Adaptor Proteins Signal Transducing Gene knockdown Lymphoid Neoplasia biology Chemistry NF-kappa B PAX5 Transcription Factor Hematology Cell biology 030104 developmental biology 030220 oncology & carcinogenesis Myeloid Differentiation Factor 88 Proto-Oncogene Proteins c-hck biology.protein Phosphorylation Chromatin immunoprecipitation Signal Transduction |
| Zdroj: | Blood Advances. 4:141-153 |
| ISSN: | 2473-9537 2473-9529 |
| DOI: | 10.1182/bloodadvances.2019000947 |
| Popis: | Hematopoietic cell kinase (HCK) is an SRC family member that is aberrantly upregulated in B-cell neoplasms dependent on MYD88-activating mutations and supports their growth and survival. We showed herein that activation of Toll-like receptor (TLR) signaling in MYD88 wild-type B cells also triggered HCK expression, denoting on path regulatory function for HCK by MYD88. To clarify the signaling cascades responsible for aberrant HCK expression in MYD88-mutated B-cell lymphomas, we performed promoter-binding transcription factor (TF) profiling, PROMO weighted TF consensus binding motif analysis, and chromatin immunoprecipitation studies. We identified PAX5, and the mutated MYD88 downstream signaling mediators STAT3, NF-κB, and AP-1, as important drivers of HCK transcription. Knockdown of PAX5, a crucial regulatory factor required for B-cell commitment and identity, abrogated HCK transcription in MYD88-mutated lymphoma cells. Among AP-1 complex components, JunB showed greatest relevance to TLR/MYD88 signaling and HCK transcription regulation. In MYD88-mutated Waldenström macroglobulinemia and activated B-cell-diffuse large B-cell lymphoma cells, knockdown of MYD88 reduced phosphorylation of JunB but not c-Jun, and knockdown of JunB reduced HCK protein levels. Deletion of STAT3, NF-κB, and AP-1 binding sites reduced corresponding TFs binding and HCK promoter activity. Moreover, inhibitors to STAT3, NF-κB, and AP-1 reduced HCK promoter activity and messenger RNA levels, particularly in combination, in MYD88-mutated lymphoma cells. The findings provide new insights into the transcriptional regulation of HCK prosurvival signaling by mutated MYD88, and the importance of JunB as a downstream mediator of the MYD88-directed signaling apparatus. |
| Databáze: | OpenAIRE |
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