Impact of chromosomal abnormalities on the efficacy of lenalidomide plus dexamethasone treatment in patients with relapsed/refractory multiple myeloma

Yoshida, Takashi; Ri, Masaki; Fujinami, Haruna; Oshima, Yoshiko; Tachita, Takuto; Marumo, Yoshiaki; Sasaki, Hirokazu; Kinoshita, Shiori; Totani, Haruhito; Narita, Takuma; Awata, Masaki; Ito, Asahi; Kusumoto, Shigeru; Ishida, Takashi; Komatsu, Hirokazu; Iida, Shinsuke

doi:10.1007/s12185-019-02669-z

Cited by 5 publications

(4 citation statements)

References 33 publications

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“…Several cytogenetic abnormalities were recently identified as high-risk markers in MM patients, including t(4;14), t(14;16), t(14;20), del(17/17p), non-hyperdiploidy of chromosome number, and gain (1q) according to IMWG risk classification 2016 [ 22 ]. This is similar to previous studies which reported that translocation involving immunoglobulin heavy chain, including t(4;14), is a common cytogenetic abnormality in high-risk MM patients [ 10 , 22 , 30 , 31 ]. Furthermore, t(4;14) was associated with an adverse prognosis in patients who received high-dose chemotherapy with autologous stem cell transplantation (ASCT) [ 32 – 34 ].…”

Section: Discussionsupporting

confidence: 92%

Targeting UCHL1 Induces Cell Cycle Arrest in High-Risk Multiple Myeloma with t(4;14)

Kamseng

Siriboonpiputtana

Puavilai

et al. 2021

Pathol. Oncol. Res.

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Multiple myeloma (MM) patients considered to be at high cytogenetic risk commonly fail to respond to standard treatment. A thorough understanding of the molecular mechanism of MM development is, therefore, needed. We endeavored to explore the transcriptional signature among different subgroups of newly diagnosed MM using gene chip-based expression microarray. Bone marrow samples of 15 newly diagnosed Thai MM patients were included. The chromosomal translocation t(4;14) was the most frequently identified genetic alteration in the high-risk subgroup. Cluster analysis from expression profiling demonstrated that high-risk MM have a distinctly different expression pattern compared to standard-risk patients. The most significant differentially expressed gene was UCHL1. Functional enrichment analysis by Gene Set Enrichment Analysis, FUNRICH, and Gene Ontology Panther pathway revealed the gene sets involved in cell cycle control to be enriched in the t(4;14) high-risk group. Interestingly, among the well-established downstream targets of UCHL1, only CCND2 was significantly expressed in the t(4;14) high-risk group. Suppression of UCHL1 protein level by LDN-5744 inhibitor could arrest the cell cycle in G1 phase in cell lines. These findings shed light on the molecular mechanism of UCHL1 in t(4;14) high-risk MM and support the evidence that alteration of the UCHL1 pathway may play a role in the pathogenesis of high-risk MM.

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Section: Discussionsupporting

confidence: 92%

Targeting UCHL1 Induces Cell Cycle Arrest in High-Risk Multiple Myeloma with t(4;14)

Kamseng

Siriboonpiputtana

Puavilai

et al. 2021

Pathol. Oncol. Res.

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“…For example, c‐FOS is known to be positively regulated by the histone H3K36 methyltransferase MMSET/NSD2, which is ectopically expressed due to the chromosome translocation t(4;14) and might contribute to the overexpression of IRF4 and SLAMF7 as a direct transactivator in high‐risk MM with t(4;14) 49,50 . Lenalidomide resistance is a well‐characterized clinical feature of MM patients with t(4;14) 51,52 and might be mediated via c‐FOS overexpression under the influence of MMSET. According to Annunziata et al., the shRNA‐mediated knockdown of MMSET reduces c‐FOS expression in t(4;14)‐harbouring MM cells 45 .…”

Section: Discussionmentioning

confidence: 99%

c‐FOS is an integral component of the IKZF1 transactivator complex and mediates lenalidomide resistance in multiple myeloma

Osada

Kikuchi

Iha

et al. 2023

Clinical & Translational Med

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BackgroundThe immunomodulatory drug lenalidomide, which is now widely used for the treatment of multiple myeloma (MM), exerts pharmacological action through the ubiquitin‐dependent degradation of IKZF1 and subsequent down‐regulation of interferon regulatory factor 4 (IRF4), a critical factor for the survival of MM cells. IKZF1 acts principally as a tumour suppressor via transcriptional repression of oncogenes in normal lymphoid lineages. In contrast, IKZF1 activates IRF4 and other oncogenes in MM cells, suggesting the involvement of unknown co‐factors in switching the IKZF1 complex from a transcriptional repressor to an activator. The transactivating components of the IKZF1 complex might promote lenalidomide resistance by residing on regulatory regions of the IRF4 gene to maintain its transcription after IKZF1 degradation.MethodsTo identify unknown components of the IKZF1 complex, we analyzed the genome‐wide binding of IKZF1 in MM cells using chromatin immunoprecipitation‐sequencing (ChIP‐seq) and screened for the co‐occupancy of IKZF1 with other DNA‐binding factors on the myeloma genome using the ChIP‐Atlas platform.ResultsWe found that c‐FOS, a member of the activator protein‐1 (AP‐1) family, is an integral component of the IKZF1 complex and is primarily responsible for the activator function of the complex in MM cells. The genome‐wide screening revealed the co‐occupancy of c‐FOS with IKZF1 on the regulatory regions of IKZF1‐target genes, including IRF4 and SLAMF7, in MM cells but not normal bone marrow progenitors, pre‐B cells or mature T‐lymphocytes. c‐FOS and IKZF1 bound to the same consensus sequence as the IKZF1 complex through direct protein‐protein interactions. The complex also includes c‐JUN and IKZF3 but not IRF4. Treatment of MM cells with short‐hairpin RNA against FOS or a selective AP‐1 inhibitor significantly enhanced the anti‐MM activity of lenalidomide in vitro and in two murine MM models. Furthermore, an AP‐1 inhibitor mitigated the lenalidomide resistance of MM cells.ConclusionsC‐FOS determines lenalidomide sensitivity and mediates drug resistance in MM cells as a co‐factor of IKZF1 and thus, could be a novel therapeutic target for further improvement of the prognosis of MM patients.

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“…Overall survival (OS) was calculated from the initiation of therapy until death from any cause. Using global RT‐PCR of bone marrow samples, the expression of three translocation‐related genes ( CCND1 , FGFR3 , and c‐MAF ) was analyzed in primary MM cells as described previously 11 …”

Section: Methodsmentioning

confidence: 99%

Comprehensive analysis of serum cytokines in patients with multiple myeloma before and after lenalidomide and dexamethasone

Tachita,

Ri,

Aoki

et al. 2024

Cancer Medicine

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Multiple myeloma (MM) is an incurable B‐cell malignancy often accompanied by profound immunodeficiency. Lenalidomide (Len) is an immunomodulatory drug that exerts promising therapeutic effects on MM through the immune system. However, predictive markers related to the effects of Len treatment are not fully understood. This study aimed to identify candidate biomarkers for predicting the clinical efficacy of Len and dexamethasone (Ld) therapy through a comprehensive analysis of serum cytokines. The levels of 48 cytokines in the serum of patients with MM just before Ld therapy (n = 77), at the time of best response (n = 56), and at disease progression (n = 49) were measured and evaluated. Patients with high IL‐18 and M‐CSF levels showed significantly shorter progression‐free survival and overall survival (OS). In contrast, patients with high PDGF‐BB levels had longer survival. Moreover, low levels of G‐CSF, IL‐7, IL‐8, and SDF‐1α were associated with shorter OS after Ld therapy. During Ld therapy, pro‐inflammatory cytokines such as IL‐2Rα, IL‐18, and TNF‐α were decreased, while IFN‐γ was increased. IL‐4 and IL‐6 levels increased during disease progression. In conclusion, this study provides a better understanding of the association between cytokines and the efficacy of Ld therapy as well as the unique changes in cytokines related to inflammatory and immune responses during Ld therapy.

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Impact of chromosomal abnormalities on the efficacy of lenalidomide plus dexamethasone treatment in patients with relapsed/refractory multiple myeloma

Cited by 5 publications

References 33 publications

Targeting UCHL1 Induces Cell Cycle Arrest in High-Risk Multiple Myeloma with t(4;14)

Targeting UCHL1 Induces Cell Cycle Arrest in High-Risk Multiple Myeloma with t(4;14)

c‐FOS is an integral component of the IKZF1 transactivator complex and mediates lenalidomide resistance in multiple myeloma

Comprehensive analysis of serum cytokines in patients with multiple myeloma before and after lenalidomide and dexamethasone

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