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Multiple myeloma (MM) is a highly heterogeneous hematologic tumor. Ubiquitin proteasome pathways (UPP) play a vital role in its initiation and development. We used cox regression analysis and least absolute shrinkage and selector operation (LASSO) to select ubiquitin proteasome pathway associated genes (UPPGs) correlated with the overall survival (OS) of MM patients in a Gene Expression Omnibus (GEO) dataset, and we formed this into ubiquitin proteasome pathway risk score (UPPRS). The association between clinical outcomes and responses triggered by proteasome inhibitors (PIs) and UPPRS were evaluated. MMRF CoMMpass was used for validation. We applied machine learning algorithms to MM clinical and UPPRS in the whole cohort to make a prognostic nomogram. Single-cell data and vitro experiments were performed to unravel the mechanism and functions of UPPRS. UPPRS consisting of 9 genes showed a strong ability to predict OS in MM patients. Additionally, UPPRS can be used to sort out the patients who would gain more benefits from PIs. A machine learning model incorporating UPPRS and International Staging System (ISS) improved survival prediction in both datasets compared to the revisions of ISS. At the single-cell level, high-risk UPPRS myeloma cells exhibited increased cell adhesion. Targeted UPPGs effectively inhibited myeloma cells in vitro. The UPP genes risk score is a helpful tool for risk stratification in MM patients, particularly those treated with PIs.

Abstract Background Multiple myeloma (MM) is an incurable hematological malignancy. Although proteasome inhibitors and immunomodulators have significantly improved patient outcomes, some patients respond poorly to treatment and almost all patients will relapse. Mechanisms of proteasome inhibitor resistance in multiple myeloma have not been fully elucidated. ZHX2 is a transcription regulator degraded via proteasome and presents both oncogenic or tumor suppressive effect in different cancers, however, it is still unknown that the role of ZHX2 in myeloma. In this study, we aim to demonstrate the effect and mechanism of ZHX2 on proteasome inhibitor resistance in MM. Methods GSE24080 gene expression profile datasets from Gene Expression Omnibus (GEO) were analyzed to evaluate the relationship between ZHX2 expression level and survival in MM. Expression of ZHX2 in human MM cell lines at baseline and after bortezomib (BTZ) treatment was determined by Western blotting (WB). The proliferation and apoptosis rate of MM cells treated with BTZ after the knockdown of ZHX2 were analyzed by flow cytometry. Nuclear translocation of NF‐κB after the knockdown of ZHX2 was evaluated by WB and immunofluorescence, and the expression of NF‐κB target genes was measured by real‐time quantitative PCR. Co‐immunoprecipitation (Co‐IP) and WB were used to detect the interaction of ZHX2 with NF‐κB. Results We found that higher ZHX2 expression was correlated with poorer clinical outcomes of patients. In addition, ZHX2 expression was relatively higher in RPMI‐8226 and MM.1S cell lines and the level of ZHX2 protein was upregulated after BTZ treatment. Knockdown of ZHX2 significantly enhanced the sensitivity of MM cells to BTZ, inhibited nuclear translocation of NF‐κB, and reduced mRNA expression of NF‐κB target genes. It was also revealed that ZHX2 directly binds to NF‐κB. Conclusion Our study showed that ZHX2 can promote proteasome inhibitor resistance in MM cells by regulating the nuclear translocation of NF‐κB.

This study attempted to investigate how clonal structure evolves, along with potential regulatory networks, as a result of multiline therapies in relapsed/refractory multiple myeloma (RRMM). Eight whole exome sequencing (WES) and one single cell RNA sequencing (scRNA-seq) were performed in order to assess dynamic genomic changes in temporal consecutive samples of one RRMM patient from the time of diagnosis to death (about 37 months). The 63-year-old female patient who suffered from MM (P1) had disease progression (PD) nine times from July 2017 [newly diagnosed (ND)] to Aug 2020 (death), and the force to drive branching-pattern evolution of malignant PCs was found to be sustained. The mutant-allele tumor heterogeneity (MATH) and tumor mutation burden (TMB) initially exhibited a downward trend, which was then upward throughout the course of the disease. Various somatic single nucleotide variants (SNVs) that had disappeared after the previous treatment were observed to reappear in later stages. Chromosomal instability (CIN) and homologous recombination deficiency (HRD) scores were observed to be increased during periods of all progression, especially in the period of extramedullary plasmacytoma. Finally, in combination with WES and scRNA-seq of P1-PD9 (the nineth PD), the intro-heterogeneity and gene regulatory networks of MM cells were deciphered. As verified by the overall survival of MM patients in the MMRF CoMMpass and GSE24080 datasets, RUNX3 was identified as a potential driver for RRMM.

Objective To explore the correlations of radiomic features of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with microvessel density (MVD) in patients with hepatocellular carcinoma (HCC), based on single-input and dual-input two-compartment extended Tofts (SITET and DITET) models. Methods We compared the quantitative parameters of SITET and DITET models for DCE-MRI in 30 patients with HCC using paired sample t -tests. The correlations of SITET and DITET model parameters with CD31-MVD and CD34-MVD were analyzed using Pearson’s correlation analysis. A diagnostic model of CD34-MVD was established and the diagnostic abilities of models for MVD were analyzed using receiver operating characteristic curve (ROC) analysis. Results There were significant differences between the quantitative parameters in the two kinds of models. Compared with SITET, DITET parameters showed better correlations with CD31-MVD and CD34-MVD. The K trans and Ve radiomics features of the DITET model showed high efficiency for predicting the level of CD34-MVD according to ROC analysis, with areas under curves of 0.83 and 0.94, respectively. Conclusion Compared with SITET, the DITET model provides a better indication of the microcirculation of HCC and is thus more suitable for examining patients with HCC.

Most patients with multiple myeloma (MM) will eventually relapse and current treatments have limited effect. Herein, we demonstrate that succinate dehydrogenase subunit A (SDHA) was low expressed in MM patients, and patients with SDHA relatively high expression had long overall survival and progression-free survival. Furthermore, SDHA high expression inhibited proliferation and invasion in MM cell lines and enhanced the anti-tumor and synergistic effect of chemotherapeutics. More importantly, chidamide was proved effective in MM by targeting SDHA, and expression of SDHA was increased by chidamide through acetylating H3K27 site of SDHA. Collectively, high expression of SDHA, which was regulated by histone acetylation and targeted by chidamide, might become a good prognostic factor of MM patients.

Immunodeficiencies are widely becoming known as important features of multiple myeloma (MM) and may promote the proliferation of malignant cells as well as confer resistance to therapy. Few studies focus on the immunomodulatory effects of the complement system on MM. This study aims to explore the role of C1q in MM patients. Plasma C1q was found to be significantly reduced in MM patients, and the amount of C1q deposited around the CD138+ cells in bone marrow (BM) biopsy sections was observed to be much higher, especially in the subgroup with 1q21 amplification (Amp1q21). CD138+ cells expressed higher levels of C1q receptors (C1qRs) than CD138− cells. Patients with Amp1q21 expressed higher levels of globular C1qR (gC1qR), whereas patients without Amp21 expressed higher levels of collagen tail C1qR (cC1qR). Additionally, gC1qR was noted to suppress the MM-inhibiting role of C1q in H929, U266, and MM1S. gC1qR interacts with insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), which also suppressed the function of C1q and regulated CDC28 protein kinase regulatory subunit 1B (CKS1B) mRNA. In summary, gC1qR suppressed the MM-inhibiting role of C1q and regulated CKS1B mRNA in promoting tumor proliferation via IGF2BP3 in 1q21-amplified MM. Our findings provide novel evidence on how MM cells evade the immune system and promote survival as well as suggest possible novel targets for future therapies of MM.