The resulting constitutive activation of NF-κB enhances the expression of adhesion molecules, such as integrin VLA-4, CD-44, P-selectin and numerous chemokines/receptors 6, 12, leading to the migration and stroma-independent growth of myeloma cells 11. Other important aberrations in EMM include the activating mutations in the NF-κB pathway genes and the homozygous deletion of the genes encoding inhibitors of this pathway 11.
Mutations in the RAS 9, KRAS, PIK3CA, ATM and NFKB2 1 genes have also been associated with the presence of EMM, including CRBN mutations leading to treatment resistance 10.
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The disruption of the TP53 gene by del(17p) and/or mutations seems to be a crucial driver of EMM (EMM vs MM: 34.5% vs 11.9%) 7, 8. Genetic studies have shown that high-risk abnormalities, such as 1q21 gain and del(1p32) (detected in > 55% of EMM patients), t(4 14) (~ 52%), MYC overexpression (~ 38%), del(17p13) (~ 35%) and del(13q14) (~ 31%), are commonly associated with EMM 1, 4, 5.
There is growing evidence that genetic factors may contribute to EMM pathogenesis and evolution 1, 4, 5. Currently, little is known about the mechanisms leading to the development of EMM, stroma-independent growth and the survival of myeloma cells at extramedullary sites or the reasons for poor treatment responses. This aggressive and mostly treatment-resistant sub-entity of MM can either accompany a newly diagnosed disease, occurring at a frequency of 3–18% 4, 5, or develop with disease progression or relapse, with a frequency of 6–20% 4, 6. Rarely, patients present with extramedullary disease (EMM), in which myeloma cells spread to other organ systems 1, 2, 3. Multiple myeloma (MM) is a clonal plasma cell proliferative disorder usually limited to a bone marrow (BM) microenvironment. Optical mapping showed the potential for refining the complex genomic architecture in MM and its phenotypes. Our pilot study revealed an association of chromosome 1 abnormalities in bone marrow myeloma cells with extramedullary progression. Widespread genomic heterogeneity and novel aberrations in the high-risk IGH/IGK/IGL, 8q24 and 13q14 regions were detected in individual patients but were not specific to EMM/MM. Compared with intramedullary MM, EMM was characterised by more deletions (size range of 500 bp–50 kbp) and fewer interchromosomal translocations, and two EMM samples had copy number loss in the 17p13 region. These rearrangements, predominantly deletions with/without inversions, encompassed hundreds of genes and led to changes in the gene copy number on large regions of chromosome 1.
Large intrachromosomal rearrangements (> 5 Mbp) within chromosome 1 were detected in all EMM samples. We used whole-genome optical mapping (Saphyr, Bionano Genomics) to analyse the genomic architecture of CD138+ cells isolated from bone-marrow aspirates from an unselected cohort of newly diagnosed patients with EMM (n = 4) and intramedullary MM (n = 7). EMM is frequently associated with high-risk cytogenetics, but their complex genomic architecture is largely unexplored. These inquiries should be directed to the clerk.Extramedullary disease (EMM) represents a rare, aggressive and mostly resistant phenotype of multiple myeloma (MM). All members accept direct briefs from in-house counsel.
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