General MM

JAM-A as a prognostic factor and new therapeutic target in MM

The tumor microenvironment has a prominent role in the progression of Multiple Myeloma (MM), with infiltrating cells providing tumor-promoting signals in the bone marrow (BM). MM cells in contact with BM stromal cells and extracellular matrix (ECM) components escape the effects of therapy through cell adhesion-mediated drug resistance. The expression profile of certain receptors is altered as a consequence of interactions between MM cells and the ECM, and one such contact-induced receptor is protein junctional adhesion molecule-A (JAM-A). JAM-A is thought to play a role in cell adhesion, migration and platelet activation, and has also been implicated in solid tumor progression. Little is known with regards to its link with MM and therefore this warranted further investigation. 

In a recent study, published in Leukemia in October 2017, Antonio Giovanni Solimando from the Department of Internal Medicine II, Interdisciplinary Center for Clinical Research Laboratory,   University Hospital of Würzburg, Germany, and colleagues evaluated the relationship between the expression levels of membrane JAM-A, progression free survival (PFS) and overall survival (OS) in 141 patients (pts) out of 147 cases.

Key Highlights:
  • Data is presented as: higher membrane JAM-A expression group (HMJE) vs lower membrane JAM-A expression (LMJE) group 
  • Pts with low JAM-A expression had a better PFS and OS than pts with high JAM-A expression
    • Median PFS = 16 months (95% CI, 13–18) vs 27 months (95% CI, 24–33), P = 0.0022
    • Median OS = 53 months (95% CI, 48–72) vs 60 months (95% CI, 48–67); P = 0.8331
    • JAM-A surface expression on MM plasma cells (MM-PCs) correlated with PFS in multivariate analysis as a predictor of disease progression; high levels were a significant risk factor for low PFS, HR = 2.347, (95% CI, 1.19–4.608)
    • JAM-A surface expression in all Newly Diagnosed MM (NDMM) subgroups (t0 =at the time of recruitment; t1= after treatment; t2 = at disease relapse) exceeded expression levels of controls, P < 0.0001
    • Membrane JAM-A was significantly higher at t2 than t1, P < 0.0001
    • Soluble (sJAM-A) was also markedly increased in MM pts compared to controls
  • JAM-A inhibition decreased MM cell migration, proliferation and survival in vitro
    • JAM-A expression was found on MM cell lines RPMI-8226 and U266, P < 0.0001, but not on other MM cell lines NCIH929, OPM-2 and INA-6, or HUVEC cells (which express JAM-A upon treatment with TNFα) as controls
    • Both JAM-A siRNA knockdown and inhibition with a blocking antibody (αJAM-A moAb) impaired:
      • MM cell migration as indicated by a scratch assay: CTRL = 61.95 ± 0.95%, siRNA = 17.78 ± 1.82%, αJAM-A = 29.33 ± 1.74%; P = 0001
      • MM cell viability: CTRL = 85%, siRNA = 67.87 and αJAM-A = 63.42%, P < 0.0001
      • MM cell proliferation: isotype vs αJAM-A moAb = 84.67±0.56% vs 65±0.58%; (95% CI, 21.46–17.88), P < 0.0001
      • Chemotaxis: isotype vs αJAM-A moAb = 67% vs 5%, P < 0.0001
      • Apoptosis: isotype vs αJAM-A moAb = 28±0.58% vs 78±0.57%; (95% CI, 48.18−51.82%), P < 0.0001
    • Treatment of MM-bearing mice with αJAM-A moAb significantly inhibited MM progression compared to untreated or isotype control: P = 0.0189

Specific targeting of JAM-A using a blocking antibody indicates that human JAM-A has an effect on MM cell proliferation both in vitro and in vivo, and could therefore be a novel target for MM, as well as a potential prognostic indicator. These preliminary pre-clinical experiments provide rationale for more comprehensive studies using a higher number of patients.  

References
  1. Solimando AG et al. JAM-A as a prognostic factor and new therapeutic target in multiple myeloma. Leukemia. 2017 Oct 24. DOI: 10.1038/leu.2017.287.
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