title: MYD88-independent growth and survival effects of Sp1 transactivation in Waldenstrom macroglobulinemia.
abstract: 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.
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Fulciniti
authors.forename: Nicola
authors.initials: N
authors.lastname: Amodio
authors.forename: Rajya Lakshmi
authors.initials: RL
authors.lastname: Bandi
authors.forename: Mansa
authors.initials: M
authors.lastname: Munshi
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Lian
authors.initials: L
authors.lastname: Xu
authors.forename: Zachary
authors.initials: Z
authors.lastname: Hunter
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Steven P
authors.initials: SP
authors.lastname: Treon
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D010957:Plasmids / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation; D008258:Waldenstrom Macroglobulinemia / Q000378:metabolism*
chemical_list: C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016329:Sp1 Transcription Factor; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse