Biology subjects

Tousseyn, T.

Publications and source records attributed to Tousseyn, T..

4 recordsLinked to original sources

bioRxiv2022

Aberrant MYCN expression drives oncogenic hijacking of EZH2 as a transcriptional activator in peripheral T cell lymphoma

Peripheral T cell lymphoma (PTCL) is a heterogeneous group of hematological cancers arising from the malignant transformation of mature T cells. In a cohort of 28 PTCL cases, we identified recurrent overexpression of MYCN, a member of the MYC family of oncogenic transcription factors. Approximately half of all PTCL cases was characterized by a MYC expression signature. Inducible expression of MYCN in lymphoid cells in a mouse model caused T cell lymphoma that recapitulated human PTCL with a MYC expression signature. Integration of mouse and human expression data identified EZH2 as a key downstream target of MYCN. Remarkably, EZH2 was found to be an essential co-factor for the transcriptional activation of the MYCN-driven gene expression program, which was independent of methyltransferase activity, but dependent on phosphorylation by CDK1. MYCN-driven T cell lymphoma was sensitive to EZH2 degradation or CDK1 inhibition, which displayed synergy with FDA-approved HDAC inhibitors. Key points- Transcriptomic analysis of PTCL tumors reveals recurrent MYCN overexpression and the presence of a MYC signature in 50% of PTCL cases - EZH2 is a transcriptional cofactor for the MYCN-driven gene expression program, which confers sensitivity to HDAC inhibition

cancer biology↗

bioRxiv2022

BET-independent MLV integration is retargeted in vivo and selects distinct genomic elements for lymphomagenesis

Moloney murine leukemia virus (MLV) infects BALB/c mice and induces T-cell lymphoma in mice. Retroviral integration is mediated by the interaction of the MLV integrase (IN) with members of the bromodomain and extra-terminal motif (BET) protein family (BRD2, BRD3 and BRD4). Introduction of the W390A mutation in MLV IN abolishes BET interaction. Here we compared the replication of W390A MLV and WT MLV in adult BALB/c mice to study the role of BET proteins in replication, integration and tumorigenesis in vivo. Comparing WT and W390A MLV infection revealed similar viral loads in blood, thymus and spleen cells. Interestingly, W390A MLV integration was retargeted away from GC-enriched genomic regions. However, both WT MLV and W390A MLV developed T cell lymphoma after a similar latency represented by an enlarged thymus and spleen and multi-organ tumor infiltration. Integration site sequencing from splenic tumor cells revealed clonal expansion in all WT MLV- and W390A MLV-infected mice. However, the integration profile of W390A MLV and WT MLV differed significantly. Integrations were enriched in enhancers and promoters but compared to WT, W390A MLV integrated less frequently into enhancers and more into oncogene bodies, such as Notch1 and Ppp1r16b. We conclude that host factors direct MLV in vivo integration site selection. Although, BET proteins target WT MLV integration preferentially towards enhancers and promoters, insertional lymphomagenesis can occur independently from BET, likely due to the intrinsically strong enhancer/promoter of the MLV LTR.

microbiology↗

bioRxiv2020

Correspondence-aware manifold learning for microscopic and spatial omics imaging: a novel data fusion method bringing MSI to a cellular resolution.

High-dimensional molecular measurements are transforming the field of pathology into a data-driven discipline. While H&E stainings are still the gold standard to diagnose disease, the integration of microscopic and molecular information is becoming crucial to advance our understanding of tissue heterogeneity. To this end, we propose a data fusion method that integrates spatial omics and microscopic data obtained from the same tissue slide. Through correspondence-aware manifold learning, we can visualise the biological trends observed in the high-dimensional omics data at microscopic resolution. While data fusion enables the detection of elements that would not be detected taking into account the separate data modalities individually, out-of-sample prediction makes it possible to predict molecular trends outside of the measured tissue area. The proposed dimensionality reduction-based data fusion paradigm will therefore be helpful in deciphering molecular heterogeneity by bringing molecular measurements such as MSI to the cellular resolution.

bioinformatics↗

bioRxiv2018

Whole-Genome Genomics Correlates of Response To Anti-PD1 Therapy in Relapsed/Refractory Natural Killer/T Cell Lymphoma

AbstractThis study aims to identify recurrent genetic alterations in relapsed or refractory (RR) natural-killer/T-cell lymphoma (NKTL) patients who have achieved complete response (CR) with programmed cell death 1 (PD-1) blockade therapy. Seven of the eleven patients treated with pembrolizumab achieved CR while the remaining four had progressive disease (PD). Using whole genome sequencing (WGS), we found recurrent clonal structural rearrangements (SR) of the PD-L1 gene in four of the seven (57%) CR patients pretreated tumors. These PD-L1 SRs consist of inter-chromosomal translocations, tandem duplication and micro-inversion that disrupted the suppressive function of PD-L1 3UTR. Interestingly, recurrent JAK3-activating (p.A573V) mutations were also validated in two CR patients tumors that did not harbor the PD-L1 SR. Importantly, these mutations were absent in the four PD cases. With immunohistochemistry (IHC), PD-L1 positivity could not discriminate patients who archived CR (range: 6%-100%) from patients who had PD (range: 35%-90%). PD-1 blockade with pembrolizumab is a potent strategy for RR NKTL patients and genomic screening could potentially accompany PD-L1 IHC positivity to better select patients for anti-PD-1 therapy.

genomics↗