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Gene expression analysis of sanroque mouse strain, a model for human follicular helper (Tfh) T-cells lymphoma

ABSTRACT: Treatment of peripheral T-cell lymphoma is inadequate but investigation of their genetics demonstrated that some are derived from normal follicular helper (Tfh) T-cells. The sanroque mouse strain bears a mutation that increases Tfh cell number and heterozygous animals (Roquinsan/+) develop lymphomas similar to human Tfh lymphoma. We have begun to characterise the lymphomas by whole exome sequencing and gene expression profiling. Interleukin-2-inducible kinase (ITK) is expressed in Tfh lymphoma and ibrutinib is a small molecule inhibitor of mouse and human ITK and a potential therapeutic agent. A preclinical study of ibrutinib in established lymphoma was then carried out and showed lymphoma regression in 8/12 (67%) of mice. Using T2-weighted MRI to assess lymph node volume and diffusion weighted MRI scanning as a measure of function, we showed that treatment increased mean apparent diffusion coefficient (ADC) suggesting cell death, and that change in ADC following treatment correlated with change in lymphoma volume. We suggest that heterozygous sanroque mice produce genetically diverse Tfh cell derived lymphomas in an immunocompetent animal and are a useful model system for preclinical testing.

ORGANISM(S): Mus musculus

PROVIDER: GSE120402 | GEO | 2018/09/26

REPOSITORIES: GEO

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Project description:Background:To evaluate the association of multiparametric and multiregional MRI-features with key molecular characteristics in patients with newly-diagnosed glioblastoma. Methods:Retrospective data evaluation was approved by the local ethics committee of the University of Heidelberg (ethics approval number: S-320/2012) and informed consent was waived. Preoperative MRI-features were correlated with key molecular characteristics within a single-institutional cohort of 152 patients with newly-diagnosed glioblastoma. Preoperative MRI-features (n=31) included multiparametric (anatomical, diffusion-, perfusion-, and susceptibility-weighted images) and multiregional (contrast enhancing and non-enhancing FLAIR-hyperintense) information with (histogram) quantification of tumor volumes, volume ratios, apparent diffusion coefficients, cerebral blood flow / volume (CBF / CBV) and intratumoral susceptibility signals. Molecular characteristics determined with the Illumina Infinium HumanMethylation450 array included global DNA-methylation subgroups (e.g. mesenchymal (MES), RTK I “PGFRA”, RTK II “classic”), MGMT-promoter methylation status and hallmark copy-number-variations (EGFR-, PDGFRA-, MDM4- and CDK4-amplification; PTEN-, CDKN2A-, NF1- and RB1-loss). Univariate analyses (voxel-lesion-symptom-mapping for tumor location, Wilcoxon-test for all other MRI-features) as well as machine-learning models were applied to study the strength of association and discriminative value of MRI-features for predicting underlying molecular characteristics. Results: There was no tumor location predilection for any of the assessed molecular parameters (permutation-adjusted p>0.05 each). Univariate imaging parameter associations were noted for EGFR amplification and CDKN2A loss, both demonstrating increased nrCBV and nrCBF values (performance of these parameters, as assessed by the area under the ROC curve ranged from 63 to 69%, FDR-adjusted p<0.05, respectively). Subjecting all MRI-features to machine-learning-based classification allowed to predict EGFR amplification status and the RTK II “classic” GB subgroup with a moderate, yet significantly greater accuracy (63% for EGFR [p<0.01] and 61% for RTK II [p=0.01]) than the prediction by chance, whereas prediction accuracy for all other molecular parameters was non-significant (p>0.05, all models). Conclusions: In summary, we found univariate associations between established MRI-features and molecular characteristics, however not of sufficient strength to allow the generation of machine-learning classification models for reliable and clinically meaningful prediction of the assessed molecular characteristics in patients with newly-diagnosed glioblastoma.

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Gene expression analysis of sanroque mouse strain, a model for human follicular helper (Tfh) T-cells lymphoma

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