MYD88-independent growth and survival effects of Sp1 transactivation in Waldenström macroglobulinemia
| Autor: | Nicola Amodio, Kenneth C. Anderson, Mariateresa Fulciniti, Pierfrancesco Tassone, Mansa Munshi, Steven P. Treon, Guang Yang, Lian Xu, Nikhil C. Munshi, Zachary R. Hunter, Rajya Lakshmi Bandi |
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| Rok vydání: | 2014 |
| Předmět: |
STAT3 Transcription Factor
Transcriptional Activation Chromatin Immunoprecipitation Cell Survival Sp1 Transcription Factor Immunology Enzyme-Linked Immunosorbent Assay Mice SCID Biology Biochemistry Mice Transactivation Cell Line Tumor Agammaglobulinaemia Tyrosine Kinase Animals Humans Transcription factor Cell Proliferation Sp1 transcription factor Lymphoid Neoplasia Cell Death Kinase Gene Expression Profiling NF-kappa B Cell Biology Hematology Protein-Tyrosine Kinases Gene Expression Regulation Neoplastic Myeloid Differentiation Factor 88 STAT protein Cancer research Waldenstrom Macroglobulinemia Signal transduction Tyrosine kinase Neoplasm Transplantation Plasmids |
| Zdroj: | Blood. 123:2673-2681 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Sp1 transcription factor controls a pleiotropic group of genes and its aberrant activation has been reported in a number of malignancies, including multiple myeloma. In this study, we investigate and report its aberrant activation in Waldenström macroglobulinemia (WM). Both loss of and gain of Sp1 function studies have highlighted a potential oncogenic role of Sp1 in WM. We have further investigated the effect of a small molecule inhibitor, terameprocol (TMP), targeting Sp1 activity in WM. Treatment with TMP inhibited the growth and survival and impaired nuclear factor-κB and signal transducer and activator of transcription activity in WM cells. We next investigated and observed that TMP treatment induced further inhibition of WM cells in MYD88 knockdown WM cells. Moreover, we observed that Bruton's tyrosine kinase, a downstream target of MYD88 signaling pathway, is transcriptionally regulated by Sp1 in WM cells. The combined use of TMP with Bruton's tyrosine kinase or interleukin-1 receptor-associated kinase 1 and 4 inhibitors resulted in a significant and synergistic dose-dependent antiproliferative effect in MYD88-L265P-expressing WM cells. In summary, these results demonstrate Sp1 as an important transcription factor that regulates proliferation and survival of WM cells independent of MYD88 pathway activation, and provide preclinical rationale for clinical development of TMP in WM alone or in combination with inhibitors of MYD88 pathway. |
| Databáze: | OpenAIRE |
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