Biology subjects

Alberge, J.-B.

Publications and source records attributed to Alberge, J.-B..

5 recordsLinked to original sources

bioRxiv2025

SVelfie: A method for discovering cancer drivers based on enrichment of likely functional structural variants

Structural variants (SVs) can drive tumorigenesis, yet discovering SV cancer drivers remains challenging1. Here, we present SVelfie (Structural Variants enriched with likely functional/impactful events), a statistical method to infer driver genes from SVs detected across a cohort of cancer genomes, based on enrichment of likely functional events. When testing SVelfie on lymphoma samples from the Pan-Cancer Analysis of Whole Genomes (PCAWG)2, it corroborates known tumor suppressor genes and also yields novel driver candidates.

bioinformatics↗

bioRxiv2023

Systematic characterization of therapeutic vulnerabilities in Multiple Myeloma with Amp1q reveals increased sensitivity to the combination of MCL1 and PI3K inhibitors

The development of targeted therapy for patients with Multiple Myeloma (MM) is hampered by the low frequency of actionable genetic abnormalities. Gain or amplification of chr1q (Amp1q) is the most frequent arm-level copy number gain in patients with MM, and it is associated with higher risk of progression and death despite recent advances in therapeutics. Thus, developing targeted therapy for patients with MM and Amp1q stands to benefit a large portion of patients in need of more effective management. Here, we employed large-scale dependency screens and drug screens to systematically characterize the therapeutic vulnerabilities of MM with Amp1q and showed increased sensitivity to the combination of MCL1 and PI3K inhibitors. Using single-cell RNA sequencing, we compared subclones with and without Amp1q within the same patient tumors and showed that Amp1q is associated with higher levels of MCL1 and the PI3K pathway. Furthermore, by isolating isogenic clones with different copy number for part of the chr1q arm, we showed increased sensitivity to MCL1 and PI3K inhibitors with arm-level gain. Lastly, we demonstrated synergy between MCL1 and PI3K inhibitors and dissected their mechanism of action in MM with Amp1q.

cancer biology↗

bioRxiv2023

Novel mechanism of MYC deregulation in Multiple Myeloma

MYC deregulation occurs in 67% of multiple myeloma (MM) cases and associates with progression and worse prognosis in MM. Enhanced MYC expression is known to be driven by translocation or amplification events, but it only occurs in 40% of MM patients. Here, we describe a new mechanism of MYC regulation, whereby epigenetic regulation of MYC by increased accessibility of a cell-type specific enhancer leads to increased MYC expression. We found enhancer activity does not associate with enhancer hijacking events. We identified specific binding of c-MAF, IRF4, and SPIB transcription factors to the enhancer can activate MYC. In addition, we discovered focal amplification of this specific enhancer in approximately 4% of MM patients. Together, our findings define a new epigenetic mechanism of MYC deregulation in MM beyond known translocations or amplifications and point to the importance of non-coding regulatory elements and their associated transcription factor networks as drivers of MM progression.

cancer biology↗

bioRxiv2021

Chromatin accessibility combined with enhancer clusters activation mediates heterogeneous response to dexamethasone in myeloma cells

Glucocorticoids (GC) effects occur through binding to the GC receptor (GR) which, once translocated to the nucleus, binds to GC response elements (GREs) to activate or repress target genes. Among GCs, dexamethasone (Dex) is widely used in treatment of multiple myeloma (MM), mainly in combination regimens. However, despite a definite benefit, all patients relapse. Moreover, while GC efficacy can be largely attributed to lymphocyte-specific apoptosis, its molecular basis remains elusive. To determine the functional role of GR binding in myeloma cells, we generated bulk and single cell multi-omic data and high-resolution contact maps of active enhancers and target genes. We show that a minority (6%) of GR binding sites are associated with enhancer activity gains and increased interaction loops. We find that enhancers contribute to regulate gene activity through combinatorial assembly of large stretches of enhancers and/or enhancer cliques. Furthermore, one enhancer, proximal to GR-responsive genes, is predominantly associated with increased chromatin accessibility and higher H3K27ac occupancy. Finally, we show that Dex exposure leads to co-accessibility changes between predominant enhancer and other regulatory regions of the interaction network. Notably, these epigenomic changes are associated with cell-to-cell transcriptional heterogeneity. As consequences, BIM critical for GR-induced apoptosis and CXCR4 protective from chemotherapy-induced apoptosis are rather upregulated in different cells. In summary, our work provides new insights into the molecular mechanisms involved in Dex escape.

cancer biology↗

bioRxiv2019

DNA hydroxymethylation reveals transcription regulation networks and prognostic signatures in multiple myeloma

Multiple myeloma (MM) is a plasma cell malignancy that remains challenging to cure despite a substantially improving median survival. During the last decade, DNA copy number variation and gene expression studies have described the pathology and its heterogeneity among patients. Epigenetic modifications play important roles in MM, but they are rarely associated with clinical aspects of the disease. In this epigenomics study, we produced quantifications of genomic 5-methylcytosine (5mC) and of 5-hydroxymethylcytosine (5hmC) as well as genome-wide maps of hydroxymethylation to analyse myeloma cells taken from a cohort of 40 newly diagnosed and homogeneously treated patients. We found 5hmC to be globally depleted in MM compared to normal plasma cells, as well as being reduced in advanced clinical stages of the disease. From the hydroxymethylome data, we observed that remaining 5hmC is organised in large peak clusters and is associated with well-known disease-related genes. Based on their signal correlation, these 5hmC peak clusters can be gathered in 2 regulation networks involving core transcription factors such as IRF4, MYC, PRDM1 and TCF3. By performing paired hydroxymethylomes at diagnosis and at relapse, we found the disease progression to be heterogeneous and patient-specific. We found that the location of 5hmC at tumor suppressor TP53INP1 is associated with better outcome while global high level of 5hmC tends to be associated with better overall survival. Together, our study suggests that 5hmC provides new biological insights of the disease severity and progression, and can be used for retrospective studies.\n\nKey PointsO_LI5hmC is globally depleted in MM and even more in advanced stages of the disease.\nC_LIO_LI5hmC is locally detected at transcriptionally active regions of MM where its presence can be associated with survival.\nC_LI

cancer biology↗