Publications by authors named "Albert Feghaly"

5 Publications

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CAMAP: Artificial neural networks unveil the role of codon arrangement in modulating MHC-I peptides presentation.

PLoS Comput Biol 2021 10 22;17(10):e1009482. Epub 2021 Oct 22.

Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Canada.

MHC-I associated peptides (MAPs) play a central role in the elimination of virus-infected and neoplastic cells by CD8 T cells. However, accurately predicting the MAP repertoire remains difficult, because only a fraction of the transcriptome generates MAPs. In this study, we investigated whether codon arrangement (usage and placement) regulates MAP biogenesis. We developed an artificial neural network called Codon Arrangement MAP Predictor (CAMAP), predicting MAP presentation solely from mRNA sequences flanking the MAP-coding codons (MCCs), while excluding the MCC per se. CAMAP predictions were significantly more accurate when using original codon sequences than shuffled codon sequences which reflect amino acid usage. Furthermore, predictions were independent of mRNA expression and MAP binding affinity to MHC-I molecules and applied to several cell types and species. Combining MAP ligand scores, transcript expression level and CAMAP scores was particularly useful to increase MAP prediction accuracy. Using an in vitro assay, we showed that varying the synonymous codons in the regions flanking the MCCs (without changing the amino acid sequence) resulted in significant modulation of MAP presentation at the cell surface. Taken together, our results demonstrate the role of codon arrangement in the regulation of MAP presentation and support integration of both translational and post-translational events in predictive algorithms to ameliorate modeling of the immunopeptidome.
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http://dx.doi.org/10.1371/journal.pcbi.1009482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577786PMC
October 2021

Atypical acute myeloid leukemia-specific transcripts generate shared and immunogenic MHC class-I-associated epitopes.

Immunity 2021 04 18;54(4):737-752.e10. Epub 2021 Mar 18.

Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3C 3J7, Canada; Department of Medicine, Université de Montréal, Montreal, QC H3C 3J7, Canada. Electronic address:

Acute myeloid leukemia (AML) has not benefited from innovative immunotherapies, mainly because of the lack of actionable immune targets. Using an original proteogenomic approach, we analyzed the major histocompatibility complex class I (MHC class I)-associated immunopeptidome of 19 primary AML samples and identified 58 tumor-specific antigens (TSAs). These TSAs bore no mutations and derived mainly (86%) from supposedly non-coding genomic regions. Two AML-specific aberrations were instrumental in the biogenesis of TSAs, intron retention, and epigenetic changes. Indeed, 48% of TSAs resulted from intron retention and translation, and their RNA expression correlated with mutations of epigenetic modifiers (e.g., DNMT3A). AML TSA-coding transcripts were highly shared among patients and were expressed in both blasts and leukemic stem cells. In AML patients, the predicted number of TSAs correlated with spontaneous expansion of cognate T cell receptor clonotypes, accumulation of activated cytotoxic T cells, immunoediting, and improved survival. These TSAs represent attractive targets for AML immunotherapy.
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http://dx.doi.org/10.1016/j.immuni.2021.03.001DOI Listing
April 2021

Targeted variant detection using unaligned RNA-Seq reads.

Life Sci Alliance 2019 08 19;2(4). Epub 2019 Aug 19.

The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Canada

Mutations identified in acute myeloid leukemia patients are useful for prognosis and for selecting targeted therapies. Detection of such mutations using next-generation sequencing data requires a computationally intensive read mapping step followed by several variant calling methods. Targeted mutation identification drastically shifts the usual tradeoff between accuracy and performance by concentrating all computations over a small portion of sequence space. Here, we present , an efficient approach leveraging k-mer decomposition of reads to identify targeted mutations. Our approach is versatile, as it can detect single-base mutations, several types of insertions and deletions, as well as fusions. We used two independent cohorts (The Cancer Genome Atlas and Leucegene) to show that mutation detection by is fast, accurate, and mainly limited by sequencing depth. Therefore, allows the establishment of fast diagnostics from next-generation sequencing data and could be suitable for clinical applications.
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http://dx.doi.org/10.26508/lsa.201900336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701478PMC
August 2019

Apoptotic endothelial cells release small extracellular vesicles loaded with immunostimulatory viral-like RNAs.

Sci Rep 2019 05 10;9(1):7203. Epub 2019 May 10.

Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, QC, H3C 3J7, Canada.

Endothelial cells have multifaceted interactions with the immune system, both as initiators and targets of immune responses. In vivo, apoptotic endothelial cells release two types of extracellular vesicles upon caspase-3 activation: apoptotic bodies and exosome-like nanovesicles (ApoExos). Only ApoExos are immunogenic: their injection causes inflammation and autoimmunity in mice. Based on deep sequencing of total RNA, we report that apoptotic bodies and ApoExos are loaded with divergent RNA cargos that are not released by healthy endothelial cells. Apoptotic bodies, like endothelial cells, contain mainly ribosomal RNA whereas ApoExos essentially contain non-ribosomal non-coding RNAs. Endogenous retroelements, bearing viral-like features, represented half of total ApoExos RNA content. ApoExos also contained several copies of unedited Alu repeats and large amounts of non-coding RNAs with a demonstrated role in autoimmunity such as U1 RNA and Y RNA. Moreover, ApoExos RNAs had a unique nucleotide composition and secondary structure characterized by strong enrichment in U-rich motifs and unstably folded RNAs. Globally, ApoExos were therefore loaded with RNAs that can stimulate a variety of RIG-I-like receptors and endosomal TLRs. Hence, apoptotic endothelial cells selectively sort in ApoExos a diversified repertoire of immunostimulatory "self RNAs" that are tailor-made for initiation of innate immune responses and autoimmunity.
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http://dx.doi.org/10.1038/s41598-019-43591-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510763PMC
May 2019

The sequence features that define efficient and specific hAGO2-dependent miRNA silencing guides.

Nucleic Acids Res 2018 09;46(16):8181-8196

Institut de recherche en immunologie et en cancérologie (IRIC), Université de Montréal, Montréal, Québec H3C 3J7, Canada.

MicroRNAs (miRNAs) are ribonucleic acids (RNAs) of ∼21 nucleotides that interfere with the translation of messenger RNAs (mRNAs) and play significant roles in development and diseases. In bilaterian animals, the specificity of miRNA targeting is determined by sequence complementarity involving the seed. However, the role of the remaining nucleotides (non-seed) is only vaguely defined, impacting negatively on our ability to efficiently use miRNAs exogenously to control gene expression. Here, using reporter assays, we deciphered the role of the base pairs formed between the non-seed region and target mRNA. We used molecular modeling to reveal that this mechanism corresponds to the formation of base pairs mediated by ordered motions of the miRNA-induced silencing complex. Subsequently, we developed an algorithm based on this distinctive recognition to predict from sequence the levels of mRNA downregulation with high accuracy (r2 > 0.5, P-value < 10-12). Overall, our discovery improves the design of miRNA-guide sequences used to simultaneously downregulate the expression of multiple predetermined target genes.
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http://dx.doi.org/10.1093/nar/gky546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144789PMC
September 2018
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