Biology subjects

Misund, K.

Publications and source records attributed to Misund, K..

4 recordsLinked to original sources

bioRxiv2025

Whole genome CRISPR knockout screen reveals ID3 as a key regulator of myeloma cell survival via TCF3 and c-MYC

Bone morphogenetic proteins (BMP) induce apoptosis in myeloma cells and the mechanism behind this could point to new therapeutic targets. Here, we did a whole genome CRISPR/Cas9 knockout screen using the INA-6 myeloma cell line. Apoptosis was induced with BMP9 and the relative amounts of sgRNAs in treated versus control cells were determined with next-generation sequencing. We identified key positive control genes and a substantial number of novel genes that could be involved in BMP-induced apoptosis. One of the overrepresented genes was the known BMP target gene ID3. We found that ID3 was potently induced by BMP9 treatment and that depletion of ID3 protected cells from c-MYC downregulation and apoptosis. ID3 is known to heterodimerize with basic helix-loop-helix (bHLH) TCF transcription factors. In the screen, TCF3, TCF4, and TCF12 were among genes that potentially protected cells from apoptosis. Knockdown of TCF3, and to some extent TCF12, led to lower basal c-MYC levels and lower cell viability, and this was more pronounced after BMP9-treatment. Our results suggest that ID3 plays an important role in regulating the survival of myeloma cells, at least in part by forming heterodimers with TCF3 and thus preventing expression of the c-MYC oncogene.

cancer biology↗

bioRxiv2025

Novel SLAMF1-derived peptide induces apoptosis in multiple myeloma cells by targeting IRF4 transcription factor for degradation

Multiple myeloma (MM) is the second most common hematological cancer. It remains incurable, highlighting the urgent need for novel therapeutic targets and treatment strategies. In this study, we investigated a panel of peptides derived from a functional motif of Signaling Lymphocytic Activation Molecule Family 1 (SLAMF1) with single amino acid substitutions and found that several of them exhibited potent anti-cancer activity by inducing MM cell death. The most potent peptide P7N4 significantly reduced the viability of both IL-6-dependent and -independent human myeloma cell lines (HMCLs), proteasome inhibitor-resistant MM cells, and primary MM cells, while exerting minimal effects on healthy blood cells. Furthermore, P7N4 enhanced the efficacy of the chemotherapeutic agent melphalan. When combined with the proteasome inhibitor bortezomib, P7N4 potentiated the anti-cancer effect of bortezomib in a highly aggressive murine MM model. Mechanistically, P7N4 induced apoptosis in MM cells by disrupting key pro-survival pathways, leading to reduction in IRF4, MYC, and {beta}-catenin levels, as well as inhibition of Akt and ERK1/2 phosphorylation. Furthermore, in peptide-sensitive HMCL, P7N4 significantly altered the expression of IRF4-associated genes. These effects were likely mediated by direct interaction of peptide with IRF4, targeting this transcription factor for degradation. Overall, our findings established P7N4 as a promising therapeutic candidate for MM, warranting further optimization and in-depth mechanistic studies.

cancer biology↗

bioRxiv2021

IL-32 is a metabolic regulator promoting survival and proliferation of malignant plasma cells

IL-32 is a non-classical cytokine expressed in cancers, inflammatory diseases and infections. IL-32 can have both extracellular and intracellular functions, and its receptor is not identified. We here demonstrate that endogenously expressed, intracellular IL-32 binds to components of the mitochondrial respiratory chain and promotes oxidative phosphorylation. Knocking out IL-32 in malignant plasma cells significantly reduced survival and proliferation in vitro and in vivo. High throughput transcriptomic and MS-metabolomic profiling of IL-32 KO cells revealed that loss of IL-32 leads to profound perturbations in metabolic pathways, with accumulation of lipids, pyruvate precursors and citrate, indicative of reduced mitochondrial function. IL-32 is expressed in a subgroup of multiple myeloma patients with an inferior prognosis. Primary myeloma cells expressing IL-32 were characterized by a plasma cell gene signature associated with immune activation, proliferation and oxidative phosphorylation. We propose a novel concept for regulation of metabolism by an intracellular cytokine and identify IL-32 as an endogenous growth and survival factor for malignant plasma cells. IL-32 is a potential prognostic biomarker and a treatment target in multiple myeloma.

cancer biology↗

bioRxiv2017

BMPR2 inhibits activin- and BMP-signaling via wild type ALK2

Activin A is a member of the TGF-{beta} superfamily and activates the transcription factors SMAD2/3 through the ALK4 type 1 receptor. Activin A has also been shown to activate SMAD1/5/8 through mutated variants of the type 1 receptor ALK2. Interestingly, we here show that both activin A and activin B could activate SMAD1/5/8 through endogenous wild type ALK2 in multiple myeloma cells. Knockdown of the type 2 receptor BMPR2 strongly potentiated activin A- and activin B-induced SMAD1/5/8 activation and subsequent cell death. Furthermore, activity of BMP6, BMP7 or BMP9, which also signal via ALK2, was potentiated by BMPR2 knockdown. Similar results were seen in HepG2 liver carcinoma cells. We propose that BMPR2 inhibited ALK2-mediated signaling by preventing ALK2 from oligomerizing with the type 2 receptors ACVR2A and ACVR2B, necessary for ALK2 activation by activins and several BMPs in these cells. In conclusion, BMPR2 could be explored as a possible target for therapy in patients with multiple myeloma.\n\nSummary StatementThe activation of SMAD1/5/8 via endogenous wild type ALK2 by activin A, activin B, and certain BMPs was enhanced when BMPR2 levels were knocked down.

cell biology↗