Genomic heterogeneity in multiple myeloma

Szalat, Raphaël; Munshi, Nikhil C.

doi:10.1016/j.gde.2015.03.008

Cited by 32 publications

(17 citation statements)

References 76 publications

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“…In MM, as in other cancers, multiple heterogeneous clones coexist, each with its own set of genetic and chromosomal abnormalities. As the disease progresses from monoclonal gammopathy of undetermined significance (MGUS) to smoldering myeloma, MM, and to plasma cell leukemia, it proliferates and develops a number of secondary CAs (Sawyer ; Keats et al, ; Morgan et al, ; Szalat and Munshi, ). Thus, it is reasonable to consume that a specific combination of abnormalities will have a greater prognostic impact than any abnormality analyzed individually.…”

Section: Introductionmentioning

confidence: 99%

Translocation t(11;14) in newly diagnosed patients with multiple myeloma: Is it always favorable?

Leiba

Duek

Amariglio

et al. 2016

Genes Chromosomes & Cancer

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The most common translocation in multiple myeloma (MM) is t(11;14)(q13;q32). According to several studies, this translocation represents a unique subset of patients with relatively favorable outcomes. Using combined analyses of morphology and fluorescence in situ hybridization (I-FISH), we examined the co-occurrence rates of t(11;14) with seven chromosomal aberrations (CAs), del(13q), del(17p), del(1p), gain(1q), multiple gains(1q), del(16q), and del(IGH), and assessed the effect of the different combinations on patient outcomes, with overall survival (OS) as the main outcome measure. Bone marrow samples and clinical data from 212 patients with MM with t(11;14) were analyzed. At least two additional CAs were found in 35% (75/205) of patients and a strong correlation between specific CAs. The occurrence of three CAs [multiple gains of (1q) (HR = 6.94, P = 0.001), del(1p) (HR = 4.47, P = 0.008), and del(IGH) (HR = 2.38, P = 0.002)] exerted a profoundly deleterious effect on median OS when compared with patients with t(11;14) only. Del(17p) and del(13q) have also exerted a deleterious effect albeit to a lesser extent (HR = 2.05, P = 0.07 and HR = 1.81, P = 0.03, respectively). When compared with t(11;14) alone, the addition of certain CAs lead to worse outcomes. These findings may have important clinical and biological implications. Patients with coexisting adverse lesions and t(11;14) may be considered at high risk and managed accordingly. © 2016 Wiley Periodicals, Inc.

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Section: Introductionmentioning

confidence: 99%

Translocation t(11;14) in newly diagnosed patients with multiple myeloma: Is it always favorable?

Leiba

Duek

Amariglio

et al. 2016

Genes Chromosomes & Cancer

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“…Multiple myeloma remains incurable, despite recent treatment advances (1). There is mounting evidence that targeting intercellular communication between malignant plasma cells or between malignant cells and host cells may enhance therapeutic outcome.…”

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confidence: 99%

Fibronectin on the Surface of Myeloma Cell-derived Exosomes Mediates Exosome-Cell Interactions

Purushothaman

Bandari²,

Liu

et al. 2016

Journal of Biological Chemistry

244

225

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Exosomes regulate cell behavior by binding to and delivering their cargo to target cells; however, the mechanisms mediating exosome-cell interactions are poorly understood. Heparan sulfates on target cell surfaces can act as receptors for exosome uptake, but the ligand for heparan sulfate on exosomes has not been identified. Using exosomes isolated from myeloma cell lines and from myeloma patients, we identify exosomal fibronectin as a key heparan sulfate-binding ligand and mediator of exosome-cell interactions. We discovered that heparan sulfate plays a dual role in exosome-cell interaction; heparan sulfate on exosomes captures fibronectin, and on target cells it acts as a receptor for fibronectin. Removal of heparan sulfate from the exosome surface releases fibronectin and dramatically inhibits exosome-target cell interaction. Antibody specific for the Hep-II heparin-binding domain of fibronectin blocks exosome interaction with tumor cells or with marrow stromal cells. Regarding exosome function, fibronectin-mediated binding of exosomes to myeloma cells activated p38 and pERK signaling and expression of downstream target genes DKK1 and MMP-9, two molecules that promote myeloma progression. Antibody against fibronectin inhibited the ability of myeloma-derived exosomes to stimulate endothelial cell invasion. Heparin or heparin mimetics including Roneparstat, a modified heparin in phase I trials in myeloma patients, significantly inhibited exosome-cell interactions. These studies provide the first evidence that fibronectin binding to heparan sulfate mediates exosomecell interactions, revealing a fundamental mechanism important for exosome-mediated cross-talk within tumor microenvironments. Moreover, these results imply that therapeutic disruption of fibronectin-heparan sulfate interactions will negatively impact myeloma tumor growth and progression.

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“…While promising, the use of NGS for clone tracking‐based detection of MM does not provide clinicians with information about genetic abnormalities associated with disease in a particular patient. Moreover, evolving clonal heterogeneity of the disease and/or clonal processes that often accelerate with age (such as monoclonal B‐cell lymphocytosis, or clonal haematopoiesis of indeterminate potential) may complicate interpretation of results obtained with clone‐tracking techniques, such as NGS (Mailankody et al , ; Szalat & Munshi, , ; Nishihori et al , ). Finally, current NGS testing works best with invasive bone marrow aspirates and may not have sufficient sensitivity to detect MRD in serum, plasma or peripheral blood (Mailankody et al , ).…”

Section: Discussionmentioning

confidence: 99%

Enumeration and characterization of circulating multiple myeloma cells in patients with plasma cell disorders

et al. 2017

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SummaryWe have developed an automated assay to enumerate and characterize circulating multiple myeloma cells (CMMC) from peripheral blood of patients with plasma cell disorders. CMMC show expression of genes characteristic of myeloma and fluorescence in situ hybridisation results on CMMC correlated well with bone marrow results. We enumerated CMMC from over 1000 patient samples including separate cohorts of newly diagnosed multiple myeloma and high/intermediate risk smouldering multiple myeloma (SMM) with clinical follow-up data. In newly diagnosed myeloma patient samples, CMMC counts correlated with other clinical measures of disease burden, including the percentage of bone marrow plasma cells, serum M protein, and International Staging System stage. CMMC counts decreased significantly from baseline when a remission was achieved due to treatment (P < 0Á001). Patients with CMMC counts ≥100 at remission showed reduced survival relative to patients with CMMC counts <100. Patients with undetectable CMMC in remission showed further overall survival benefits. In the SMM cohort, there was a trend toward higher CMMC in patients with higher-risk myeloma precursor states. Significantly higher CMMC counts were observed between intermediate/high risk SMM patients that progressed versus those without progression (P = 0Á031). CMMC allow a non-invasive means of monitoring tumour biology and may have use as a prognostic test for patients with plasma cell disorders.

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Genomic heterogeneity in multiple myeloma

Cited by 32 publications

References 76 publications

Translocation t(11;14) in newly diagnosed patients with multiple myeloma: Is it always favorable?

Translocation t(11;14) in newly diagnosed patients with multiple myeloma: Is it always favorable?

Fibronectin on the Surface of Myeloma Cell-derived Exosomes Mediates Exosome-Cell Interactions

Enumeration and characterization of circulating multiple myeloma cells in patients with plasma cell disorders

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