Identification of Circulating Serum Multi-MicroRNA Signatures in Human DLBCL Models

Abstract

There remains a need to identify new sensitive diagnostic and predictive blood-based platforms in lymphoma. We previously discovered a novel circulating microRNA (miRNA) signature in a Smurf2-deficient mouse model that spontaneously develops diffuse large B-cell lymphoma (DLBCL). Herein, we investigated this 10-miRNA signature (miR-15a, let-7c, let-7b, miR-27a, miR-10b, miR-18a, miR-497, miR-130a, miR24, and miR-155) in human lymphoma cell lines, mice engrafted with patient-derived xenografts (PDXs), and DLBCL patient serum samples leveraging systems biology analyses and droplet digital PCR (ddPCR) technology. Overall, 90% of the miRNAs were enriched in PDX DLBCL models and human lymphoma cell lines. Circulating miRNAs from the serum of 86 DLBCL patients were significantly increased compared with healthy controls and had similar patterns to the murine models. Strikingly, miRNAs were identified up to 27-fold higher levels in the serum of PDX-bearing mice and human patients compared with lymphoma cell lysates, suggesting a concentration of these factors over time within sera. Using cut-points from recursive partitioning analysis, we derived a 5-miRNA signature (let-7b, let-7c, miR-18a, miR-24, and miR-15a) with a classification rate of 91% for serum from patients with DLBCL versus normal controls. In addition, higher levels of circulating let-7b miRNA were associated with more advanced stage disease (i.e., III-IV vs. I-II) in DLBCL patients and higher levels of miR-27a and miR-24 were associated with MYC rearrangement. Taken together, circulating multi-miRNAs were readily detectable in pre-clinical cell line and human lymphoma models as well as in DLBCL patients where they appeared to distinguish clinico-pathologic subtypes and disease features.

Beyond Low-Earth Orbit: Characterizing Immune and microRNA Differentials following Simulated Deep Spaceflight Conditions in Mice

“…Due to their important role in gene expression regulation ( O'Brien et al., 2018 ), contribution to immunity ( Tsitsiou and Lindsay, 2009 ), and importance for therapeutic purposes ( van Rooij and Kauppinen, 2014 ), we sought to assess the circulating miRNA profile expressed in the plasma following simulated deep space exposures. We focused on miRNAs in plasma, as we have demonstrated that the immune system dysregulation is systemic and circulating ( Beheshti et al., 2017 , 2018 , 2019 ; Mehta and Baltimore, 2016 ; Montagner et al., 2013 ; Schwarzenbach and Gahan, 2019 ). To determine the overall impact that miRNAs have on the immune system, we first predicted gene ontology (GO) terms with an false discovery rate < 0.05 from processed miRNA-sequenced plasma data for all conditions and filtered for specific immune GO terms ( Figure 7 ).…”

LET-Dependent Low Dose and Synergistic Inhibition of Human Angiogenesis by Charged Particles: Validation of miRNAs that Drive Inhibition

“…The synergistic effect of heavy and light ions together is a highly complex response that requires control by key regulators. We have previously identified and validated a spaceflight signature of circulating miRNAs associated with cardiovascular damage ( Beheshti et al., 2018 , 2019 ; Malkani et al., 2020 ). We have also shown that these circulating miRNAs can be systemic drivers in the host to promote increased health risks due to heavy and light ion exposure ( Malkani et al., 2020 ; Paul et al, 2020 ).…”

“…We have previously identified and validated a spaceflight signature of three specific miRNAs associated with cardiovascular damage: these are let-7a-5p, miR-125b-5p, and miR-16-5p ( Beheshti et al., 2018 , 2019 ; Malkani et al., 2020 ). We found that these miRNAs were upregulated in mature micro-vessels and validated as effectors of simGCRsim-induced micro-vessel collapse ( Malkani et al., 2020 ).…”

miRNA signature associated with R–CHOP refractoriness in patients diagnosed with diffuse large B cell lymphoma

“…In addition, pathways and processes associated to drug resistance were regulated as well by the miRNAs here found, such as the fatty acid biosynthesis and metabolism. Fatty acid receptor GPCR120, has been described as responsible to up-regulate ABC transporters and trigger chemoresistance in breast cancer [ 29 ], and the fatty acid synthase was reported to be involved in DLBCL progression [ 30 ]. In addition, the neurotrophin TRK receptor signaling has also found to be regulated by these miRNAs, being associated to a more aggressive DLBCL phenotype, rituximab-resistance and pro-survival response to chemotherapeutic agents [ [31] , [32] , [33] , [34] , [35] ].…”