菊池 次郎

Multiple myeloma (MM) is the second most common hematologic malignancy and has a poor prognosis. Although the outcomes of MM have markedly improved with the approval of novel agents, the high incidence of relapse means that MM remains incurable. The bone marrow microenvironment (BMME) contributes to drug resistance and minimal residual disease (MRD), which is a major source of relapse in patients with MM. However, the underlying molecular mechanisms are not fully understood. We have previously shown that the upregulation of the AP-1 transcription factor c-FOS confers lenalidomide resistance by maintaining IRF4 expression in MM cells. In this study, we show that upregulated expression of c-FOS confers a poor prognosis and cancer stem cell-like features, including drug resistance, within BMME, both in vitro and in vivo, via IRF4 upregulation; and that inhibition of c-FOS by the AP-1 inhibitor, T-5224, prevents regeneration of MM cells via IRF4 downregulation in a murine serial transplantation assay. These results suggest a functional role for c-FOS in conferring cancer stem cell-like features to MM cells in the BMME for the first time. Therefore, c-FOS inhibition may be an effective treatment strategy for improving the outcomes of patients with MM by eliminating drug-resistant cancer stem cell-like MM cells in MRD.

<jats:title>Abstract</jats:title> <jats:p>The development of mRNA vaccines and oral drugs against SARS-CoV-2 has been useful in protecting against Covid-19 infection. Since then, however, many variants of delta and omicron strains with enhanced infectivity and immune escape capacity have emerged. A 7-amino acid random peptide ribosome display library screening system was used to perform a rapid in vitro screening of peptide aptamers that universally bind to the SARS-CoV-2 wild-type, delta, and Omicron variant BA.1, BA.2, and BA.5 spike RBD (Receptor Binding Domain). Screening resulted in four peptide aptamers that showed positive binding reactions in ELISA. Interestingly, Amino Acid Sequence Determination of the four clones predicted that three of the four clones contain 2 ~ 3 Cys residues in their sequences, forming a complex higher-order structure with disulfide (S-S) bonds. The 7-amino acid random peptide ribosome display library screening system allows for rapid in vitro screening of peptide aptamers that bind to other unknown emerging infectious disease pathogens that may be pandemic in the future. The peptide aptamers are as small as 30 amino acids and can be easily synthesized and purified as peptides or proteins, or simply used as mRNA drugs.</jats:p>