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Intratumor Heterogeneity of MIF Expression Correlates With Extramedullary Involvement of Multiple Myeloma.

ABSTRACT: Macrophage migration inhibitory factor (MIF) has been shown to promote disease progression in many malignancies, including multiple myeloma (MM). We previously reported that MIF regulates MM bone marrow homing and knockdown of MIF favors the extramedullary myeloma formation in mice. Here, based on MIF immunostaining of myeloma cells in paired intramedullary and extramedullary biopsies from 17 patients, we found lower MIF intensity in extramedullary MM (EMM) versus intramedullary MM (IMM). Flow cytometry and histology analysis in xenograft models showed a portion of inoculated human MM cells lost their MIF expression (MIF^Low) in vivo. Of note, IMM had dominantly MIF^High cells, while EMM showed a significantly increased ratio of MIF^Low cells. Furthermore, we harvested the extramedullary human MM cells from a mouse and generated single-cell transcriptomic data. The developmental trajectories of MM cells from the MIF^High to MIF^Low state were indicated. The MIF^High cells featured higher proliferation. The MIF^Low ones were more quiescent and harbored abundant ribosomal protein genes. Our findings identified in vivo differential regulation of MIF expression in MM and suggested a potential pathogenic role of MIF in the extramedullary spread of disease.

SUBMITTER: Xu J

PROVIDER: S-EPMC8276700 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Intratumor Heterogeneity of MIF Expression Correlates with Extramedullary Involvement of Multiple Myeloma

Project description:Macrophage migration inhibitory factor (MIF) has been shown to promote disease progression in many malignancies, including multiple myeloma (MM). We previously reported that MIF regulates MM bone marrow homing and knockdown of MIF favors the extramedullary myeloma formation in mice. Here, based on MIF immunostaining of myeloma cells in paired intramedullary and extramedullary biopsies from 17 patients, we found lower MIF intensity in extramedullary MM (EMM) versus intramedullary MM (IMM). Flow cytometry and histology analysis in ARD cell line-derived xenograft models showed a portion of inoculated human MM cells lost their MIF expression (MIFLow) in vivo. Of note, IMM had dominantly MIFHigh cells, while EMM showed a significantly increased ratio of MIFLow cells. We harvested the extramedullary human MM cells from a mouse and generated single-cell transcriptomic data. The developmental trajectories of MM cells from the MIFHigh to MIFLow state were indicated. The MIFHigh cells featured higher proliferation. The MIFLow ones were more quiescent and harbored abundant ribosomal protein genes. Our findings identified in vivo differential regulation of MIF expression in MM and suggested a potential pathogenic role of MIF in the extramedullary spread of disease.

2021-07-20 | GSE175660 | GEO

Intratumor Heterogeneity of MIF Expression Correlates with Extramedullary Involvement of Multiple Myeloma

Project description:Intratumor Heterogeneity of MIF Expression Correlates with Extramedullary Involvement of Multiple Myeloma

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Involvement of Small Non-Coding RNA and Cell Antigens in Pathogenesis of Extramedullary Multiple Myeloma.

Project description:Extramedullary multiple myeloma (EMD) is an aggressive disease; malignant plasma cells lose their dependence in the bone marrow microenvironment and migrate into tissues. EMD is a negative prognostic factor of survival. Using flow cytometry and next-generation sequencing, we aimed to identify antigens and microRNAs (miRNAs) involved in EMD pathogenesis. Flow cytometry analysis revealed significant differences in the level of clonal plasma cells between MM and EMD patients, while the expression of CD markers was comparable between these two groups. Further, miR-26a-5p and miR-30e-5p were found to be significantly down-regulated in EMD compared to MM. Based on the expression of miR-26a-5p, we were able to distinguish these two groups of patients with high sensitivity and specificity. In addition, the involvement of deregulated miRNAs in cell cycle regulation, ubiquitin-mediated proteolysis and signaling pathways associated with infections or neurological disorders was observed using GO and KEGG pathways enrichment analysis. Subsequently, a correlation between the expression of analyzed miRNAs and the levels of CD molecules was observed. Finally, clinicopathological characteristics as well as CD antigens associated with the prognosis of MM and EMD patients were identified. Altogether, we identified several molecules possibly involved in the transformation of MM into EMD.

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Extramedullary multiple myeloma PDX

Project description:Extramedullary multiple myeloma patient-derived orthotopic xenograft with a highly disturbed genome: combined exhaustive molecular and therapeutic studies

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Expression data of newly diagnosed multiple myeloma and extramedullary myeloma

Project description:Despite the development of novel therapeutic agents, multiple myeloma (MM) remains incurable, owing mainly to inevitable relapse in almost all patients. Some relapses occur as extramedullary disease (EMD), which is rare but is the most aggressive event in MM patients. Extramedullary myeloma (EMM) has extraordinary heterogeneous biological and clinical features. Previous studies have shown that expression levels of LncRNAs and mRNAs in different stages of MM are different. This study analyzes the expression levels of LncRNAs and mRNAs in primary plasma cells (PCs) from MM and EMM patients.

2023-03-01 | GSE147841 | GEO

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Project description:The dismal outcome of pleuropericardial extramedullary multiple myeloma (EMM) reflects both the selection of resistant disease and absence of useful drugs. Carfilzomib and dexamethasone should be explored in advanced EMM patients, even for bortezomib-resistant patients, as may provide much longer overall survival than previously reported treatments.

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Chromothripsis 18 in multiple myeloma patient with rapid extramedullary relapse.

Project description:Background:Catastrophic chromosomal event known as chromothripsis was proven to be a significant hallmark of poor prognosis in several cancer diseases. While this phenomenon is very rare in among multiple myeloma (MM) patients, its presence in karyotype is associated with very poor prognosis. Case presentation:In our case, we report a 62 year female patient with rapid progression of multiple myeloma (MM) into extramedullary disease and short overall survival (OS?=?23 months). I-FISH investigation revealed presence of gain 1q21 and hyperdiploidy (+?5,+?9,+?15) in 82% and 86%, respectively, while IgH rearrangements, del(17)(p13) and del(13)(q14) were evaluated as negative.Whole-genome profiling using array-CGH showed complex genomic changes including hyperdiploidy (+?3,+?5,+?9,+?11, +?15,+?19), monosomy X, structural gains (1q21-1q23.1, 1q32-1q44, 16p13.13-16p11.2) and losses (1q23.1-1q32.1; 8p23.3-8p11.21) of genetic material and chromothripsis in chromosome 18 with 6 breakpoint areas. Next-generation sequencing showed a total of 338 variants with 1.8% (6/338) of pathological mutations in NRAS (c.181C?>?A; p.Gln61Lys) or variants of unknown significance in TP53, CUX1 and POU4F1. Conclusions:Our findings suggest that presence of chromothripsis should be considered as another important genetic hallmark of poor prognosis in MM patients and utilization of genome-wide screening techniques such as array-CGH and NGS improves the clinical diagnostics of the disease.

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Advances in the treatment of extramedullary disease in multiple myeloma.

Project description:Extramedullary disease (EMD) is characterized by plasma cells outside of bone marrow in multiple myeloma (MM) patients, which results in an adverse prognosis. The cornerstone of treatment consists of combination therapy including proteasome inhibitors, immunomodulatory agents, steroids, followed by consolidative autologous hematopoietic stem cell transplantation in eligible patients. This review summarized the recent advances in the treatment of EMD. Bortezomib based therapy showed efficacy and was recommended to treat EMD. Marizomib had advantages in the treatment of central nervous system-multiple myeloma (CNS-MM) because of its good central nervous system penetrability. Immunomodulatory drugs such as lenalidomide and pomalidomide have been reported to be effective. Isatuximab and selinexor were also active. Based on the treatment experience of EMD in our department, we summarized treatment approach for EMD. However, the benefits of patients with EMD from the new era of novel drugs were limited. Novel drugs combination, monoclonal antibody, molecular targeted therapy, cellular immunotherapy and autologous stem cell transplantation (ASCT) are under investigation. Therapeutic studies and clinical trials specifically target EMD should be conducted. Hopefully, these treatment options for EMD will be demonstrated efficacy in the future.

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Correlation Between Uptake of <sup>18</sup>F-FDG During PET/CT and Ki-67 Expression in Patients Newly Diagnosed With Multiple Myeloma Having Extramedullary Involvement.

Project description:The aim of this study was to evaluate the relationship of prognosis of patients with multiple myeloma having extramedullary involvement (EMM) with the 18F- fluorodeoxyglucose(18F-FDG) maximum standardized uptake value and the expression of Ki-67 in biopsy samples. Sixty-five patients were newly diagnosed with multiple myeloma presenting with EMM at our hospital from January 2005 to January 2015. Of these 65 patients, 20 were enrolled in this study. Over the last decade, both the maximum standardized uptake value and Ki-67 expression in these extramedullary lesions significantly correlated with progression-free survival, respectively ( P= .039, P =.009). After combining-the maximum standardized uptake value and the Ki-67 expression as an integral-there was a significant correlation between both the overall survival ( P = .027) and progression-free survival ( P= .014). Patients have poor outcomes when EMM is detected at presentation. Both the maximum standardized uptake value and Ki-67 expression could aid in accurately evaluating EMM patient prognosis.

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Intratumor Heterogeneity in Uveal Melanoma BAP-1 Expression.

Project description:Malignant tumors are rarely homogenous on the morphological, genome, transcriptome or proteome level. In this study, we investigate the intratumor heterogeneity of BAP-1 expression in uveal melanoma with digital image analysis of 40 tumors. The proportion of BAP-1 positive cells was measured in full tumor sections, hot spots, cold spots and in scleral margins. The mean difference between hot spots and cold spots was 41 percentage points (pp, SD 29). Tumors with gene expression class 1 (associated with low metastatic risk) and 2 (high metastatic risk) had similar intratumor heterogeneity. Similarly, the level of intratumor heterogeneity was comparable in tumors from patients that later developed metastases as in patients that did not. BAP-1 measured in any tumor region added significant prognostic information to both American Joint Committee on Cancer (AJCC) tumor size category (p ≤ 0.001) and gene expression class (p ≤ 0.04). We conclude that there is substantial intratumor heterogeneity in uveal melanoma BAP-1 expression. However, it is of limited prognostic importance. Regardless of region, analysis of BAP-1 expression adds significant prognostic information beyond tumor size and gene expression class.

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