Expression, mutation, and methylation of cereblon‐pathway genes at pre‐ and post‐lenalidomide treatment in multiple myeloma

Tachita, Takuto; Kinoshita, Shiori; Ri, Masaki; Aoki, Sho; Asano, Arisa T.; Kanamori, Takashi; Yoshida, Takashi; Totani, Haruhito; Ito, Asahi; Kusumoto, Shigeru; Komatsu, Hirokazu; Yamagata, Kazufumi; Kubo, Kohmei; Tohkin, Masahiro; Fukuda, Shinsaku; Iida, Shinsuke

doi:10.1111/cas.14352

Cited by 19 publications

(21 citation statements)

References 32 publications

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“…In recent years, The dysregulation and/or prognostic roles of KPNA2 were reported in many tumors including esophageal squamous cell carcinoma (Song et al, 2019), breast cancer (Groheux et al, 2018;Wang et al, 2019a), myeloma (Kriegsmann et al, 2019;Tachita et al, 2020), clear cell renal cell carcinoma (Müller et al, 2019), oral cancer (Wang et al, 2018), bladder cancer (Jeong et al, 2017), and colorectal cancer (Ostasiewicz et al, 2016;Jeong et al, 2017). The immune-related roles of KPNA2 were also shown in tumors.…”

Section: Introductionmentioning

confidence: 99%

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

Zhang

Gao

et al. 2020

Front. Genet.

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Karyopherin α2 (KPNA2) was reported to be overexpressed and have unfavorable prognostic effects in many malignancies including hepatocellular carcinoma (HCC). Although its contributions to inflammatory response were reported in many studies, its specific associations with immune infiltrations and immune pathways during cancer progression were unclear. Here, we aimed to identify new markers for HCC diagnosis and prognosis through KPNA2-associated immune analyses. RNA-seq expression data of HCC datasets were downloaded from The Cancer Genome Atlas and International Cancer Genome Consortium. The gene expressions were counts per million normalized. The infiltrations of 24 kinds of immune cells in the samples were evaluated with ImmuCellAI (Immune Cell Abundance Identifier). The Spearman correlations of the immune infiltrations with KPNA2 expression were investigated, and the specific positive correlation of B-cell infiltration with KPNA2 expression in HCC tumors was identified. Fifteen genes in KEGG (Kyoto Encyclopedia of Genes and Genomes) B-cell receptor signaling pathway presented significant correlations with KPNA2 expression in HCC. Among them, GRB2 and NRAS were indicated to be independent unfavorable prognostic factors for HCC overall survival. Clinical Proteomic Tumor Analysis Consortium HCC dataset was investigated to validate the results at protein level. The upregulation and unfavorable prognostic effects of KPNA2 and GRB2 were confirmed, whereas, unlike its mRNA form, NRAS protein was presented to be downregulated and have favorable prognostic effects. Through receiver operating characteristic curve analysis, the diagnostic potential of the three proteins was shown. The RNA-binding proteins (RBPs) of KPNA2, NRAS, and GRB2, downloaded via The Encyclopedia of RNA Interactomes, were investigated for their clinical significance in HCC at protein level. An eight-RBP signature with independent prognostic value and dysregulations in HCC was identified. All the RBPs were significantly correlated with MKI67 expression and at least one of KPNA2, GRB2, and NRAS at protein level in HCC, indicating Zhang et al. KPNA2-Associated Immune Analyses in HCC Frontiers in Genetics | www.frontiersin.org 2 October 2020 | Volume 11 | Article 593273 their roles in HCC progression and the regulation of the three proteins. We concluded that KPNA2, GRB2, NRAS, and their RBPs might have coordinating roles in HCC immunoregulation and progression. They might be new markers for HCC diagnosis and prognosis predication and new targets for HCC immunotherapy.

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Section: Introductionmentioning

confidence: 99%

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

Zhang

Gao

et al. 2020

Front. Genet.

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“…DNA samples from the bone marrow of IMiD and PI doublerefractory MM patients have been examined using nextgeneration sequencing, and CRBN pathway-related mutations were identified in 32.5% of the patients [18]. Other reports have shown that most patients treated with lenalidomide have downregulated CRBN and upregulated IKZF1 gene expression [19]. CRBN mutations are also associated with pomalidomide resistance in MM [20].…”

Section: Introductionmentioning

confidence: 99%

Small-molecule HDAC and Akt inhibitors suppress tumor growth and enhance immunotherapy in multiple myeloma

Hirano

Imai

Kaito

et al. 2021

J Exp Clin Cancer Res

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Background Multiple myeloma (MM) is an incurable disease. The acquisition of resistance to drugs, including immunomodulatory drugs (IMiDs), has a negative effect on its prognosis. Cereblon (CRBN) is a key mediator of the bioactivities of IMiDs such as lenalidomide. Moreover, genetic alteration of CRBN is frequently detected in IMiD-resistant patients and is considered to contribute to IMiD resistance. Thus, overcoming resistance to drugs, including IMiDs, is expected to improve clinical outcomes. Here, we examined potential mechanisms of a histone deacetylase (HDAC) inhibitor and Akt inhibitor in relapsed/refractory MM patients. Methods We established lenalidomide-resistant cells by knocking down CRBN with RNAi-mediated downregulation or knocking out CRBN using CRISPR-Cas9 in MM cells. Additionally, we derived multi-drug (bortezomib, doxorubicin, or dexamethasone)-resistant cell lines and primary cells from relapsed/refractory MM patients. The effects of HDAC and Akt inhibitors on these drug-resistant MM cells were then observed with a particular focus on whether HDAC inhibitors enhance immunotherapy efficacy. We also investigated the effect of lenalidomide on CRBN-deficient cells. Results The HDAC inhibitor suppressed the growth of drug-resistant MM cell lines and enhanced the antibody-dependent cellular cytotoxicity (ADCC) of therapeutic antibodies by upregulating natural killer group 2D (NKG2D) ligands in MM cells. CRBN-deficient cells showed lenalidomide-induced upregulation of phosphorylated glycogen synthase kinase-3 (p-GSK-3) and c-Myc phosphorylation. Moreover, HDAC and Akt inhibitors downregulated c-Myc by blocking GSK-3 phosphorylation. HDAC and Akt inhibitors also exhibited synergistic cytotoxic and c-Myc-suppressive effects. The dual HDAC and PI3K inhibitor, CUDC-907, exhibited cytotoxic and immunotherapy-enhancing effects in MM cells, including multi-drug-resistant lines and primary cells from lenalidomide-resistant patients. Conclusions The combination of an HDAC and an Akt inhibitor represents a promising approach for the treatment of relapsed/refractory MM.

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“…Immunomodulatory drugs such as thalidomide, lenalidomide, and pomalidomide modulate the inflammatory environment of the bone marrow, causing MM cell death by inhibiting angiogenesis and antiproliferative properties [ 22 ]. Cereblon (CRBN) is a target for immunomodulatory drugs [ 23 ], and lenalidomide-bound cereblon acquires the ability to target two specific B cell transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3), for proteasomal degradation [ 24 ]. Another promising treatment for MM is anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy.…”

Section: Multiple Myeloma Is the Second Most Common Hematological Malignancy: Current Treatment Strategiesmentioning

confidence: 99%

Treatment of Multiple Myeloma and the Role of Melphalan in the Era of Modern Therapies—Current Research and Clinical Approaches

Poczta

Rogalska

Marczak

2021

JCM

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Multiple myeloma (MM) accounts for 10% of all hematological malignancies, and it is the second most common hematological neoplasm for which chemotherapy is an important pharmacological treatment. High dose melphalan followed by autologous stem cell transplantation remains the standard of treatment for transplant-eligible patients with MM. In this review, we describe aspects of the pharmacokinetics and pharmacodynamics of melphalan therapy and related compounds. In addition, we describe the use of melphalan in innovative therapies for the treatment of MM, including the development of drug carriers to reduce systemic toxicity, combination therapy to improve the effectiveness of cancer therapy, and the chemical modification of the melphalan molecule to improve antitumor activity.

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Expression, mutation, and methylation of cereblon‐pathway genes at pre‐ and post‐lenalidomide treatment in multiple myeloma

Cited by 19 publications

References 32 publications

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

Small-molecule HDAC and Akt inhibitors suppress tumor growth and enhance immunotherapy in multiple myeloma

Treatment of Multiple Myeloma and the Role of Melphalan in the Era of Modern Therapies—Current Research and Clinical Approaches

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