Sébastien Lemieux

Jean-Jacques Dunyach

Pierre Thibault

2022-08-22

Analytical Chemistry (publié)

Two types of human TCR differentially regulate reactivity to self and non-self antigens

Assya Trofimov

Philippe Brouillard

Jean-David Larouche

Jonathan Séguin

Jean-Philippe Laverdure

Ann Brasey

Grégory Ehx

Denis-Claude Roy

Lambert Busque

Silvy Lachance

Claude Perreault

2022-08-17

iScience (publié)

Induced pluripotent stem cells display a distinct set of MHC I-associated peptides shared by human cancers

Anca Apavaloaei

Leslie Hesnard

Marie-Pierre Hardy

Basma Benabdallah

Grégory Ehx

Catherine Thériault

Jean-Philippe Laverdure

Chantal Durette

Joël Lanoix

Mathieu Courcelles

Nandita Noronha

Kapil Dev Chauhan

Christian Beauséjour

Mick Bhatia

Pierre Thibault

Claude Perreault

2022-08-01

Cell Reports (publié)

Two types of human TCR differentially regulate reactivity to self and non-self antigens

Assya Trofimov

Philippe Brouillard

Jean-David Larouche

Jonathan Y. Séguin

Jean-Philippe Laverdure

A. Brasey

Grégory Ehx

D. Roy

Lambert Busque

Silvy Lachance

Claude Perreault

2022-04-28

bioRxiv (preprint)

Monoallelic Heb/Tcf12 Deletion Reduces the Requirement for NOTCH1 Hyperactivation in T-Cell Acute Lymphoblastic Leukemia

Diogo F. T. Veiga

Mathieu R. Tremblay

Bastien Gerby

Sabine Herblot

André Haman

Patrick Gendron

J. Zúñiga-Pflücker

Josée Hébert

Joseph Paul Cohen

T. Hoang

Early T-cell development is precisely controlled by E proteins, that indistinguishably include HEB/TCF12 and E2A/TCF3 transcription factors,… (voir plus) together with NOTCH1 and pre-T cell receptor (TCR) signalling. Importantly, perturbations of early T-cell regulatory networks are implicated in leukemogenesis. NOTCH1 gain of function mutations invariably lead to T-cell acute lymphoblastic leukemia (T-ALL), whereas inhibition of E proteins accelerates leukemogenesis. Thus, NOTCH1, pre-TCR, E2A and HEB functions are intertwined, but how these pathways contribute individually or synergistically to leukemogenesis remain to be documented. To directly address these questions, we leveraged Cd3e-deficient mice in which pre-TCR signaling and progression through β-selection is abrogated to dissect and decouple the roles of pre-TCR, NOTCH1, E2A and HEB in SCL/TAL1-induced T-ALL, via the use of Notch1 gain of function transgenic (Notch1ICtg) and Tcf12+/- or Tcf3+/- heterozygote mice. As a result, we now provide evidence that both HEB and E2A restrain cell proliferation at the β-selection checkpoint while the clonal expansion of SCL-LMO1-induced pre-leukemic stem cells in T-ALL is uniquely dependent on Tcf12 gene dosage. At the molecular level, HEB protein levels are decreased via proteasomal degradation at the leukemic stage, pointing to a reversible loss of function mechanism. Moreover, in SCL-LMO1-induced T-ALL, loss of one Tcf12 allele is sufficient to bypass pre-TCR signaling which is required for Notch1 gain of function mutations and for progression to T-ALL. In contrast, Tcf12 monoallelic deletion does not accelerate Notch1IC-induced T-ALL, indicating that Tcf12 and Notch1 operate in the same pathway. Finally, we identify a tumor suppressor gene set downstream of HEB, exhibiting significantly lower expression levels in pediatric T-ALL compared to B-ALL and brain cancer samples, the three most frequent pediatric cancers. In summary, our results indicate a tumor suppressor function of HEB/TCF12 in T-ALL to mitigate cell proliferation controlled by NOTCH1 in pre-leukemic stem cells and prevent NOTCH1-driven progression to T-ALL.

2022-03-24

Frontiers in Immunology (published)

Monoallelic Heb/Tcf12 Deletion Reduces the Requirement for NOTCH1 Hyperactivation in T-Cell Acute Lymphoblastic Leukemia

Diogo F. T. Veiga

Mathieu Tremblay

Bastien Gerby

Sabine Herblot

André Haman

Patrick Gendron

Juan Carlos Zúñiga-Pflücker

Josée Hébert

Joseph Paul Cohen

Trang Hoang

Early T-cell development is precisely controlled by E proteins, that indistinguishably include HEB/TCF12 and E2A/TCF3 transcription factors,… (voir plus) together with NOTCH1 and pre-T cell receptor (TCR) signalling. Importantly, perturbations of early T-cell regulatory networks are implicated in leukemogenesis. NOTCH1 gain of function mutations invariably lead to T-cell acute lymphoblastic leukemia (T-ALL), whereas inhibition of E proteins accelerates leukemogenesis. Thus, NOTCH1, pre-TCR, E2A and HEB functions are intertwined, but how these pathways contribute individually or synergistically to leukemogenesis remain to be documented. To directly address these questions, we leveraged Cd3e-deficient mice in which pre-TCR signaling and progression through β-selection is abrogated to dissect and decouple the roles of pre-TCR, NOTCH1, E2A and HEB in SCL/TAL1-induced T-ALL, via the use of Notch1 gain of function transgenic (Notch1ICtg) and Tcf12+/- or Tcf3+/- heterozygote mice. As a result, we now provide evidence that both HEB and E2A restrain cell proliferation at the β-selection checkpoint while the clonal expansion of SCL-LMO1-induced pre-leukemic stem cells in T-ALL is uniquely dependent on Tcf12 gene dosage. At the molecular level, HEB protein levels are decreased via proteasomal degradation at the leukemic stage, pointing to a reversible loss of function mechanism. Moreover, in SCL-LMO1-induced T-ALL, loss of one Tcf12 allele is sufficient to bypass pre-TCR signaling which is required for Notch1 gain of function mutations and for progression to T-ALL. In contrast, Tcf12 monoallelic deletion does not accelerate Notch1IC-induced T-ALL, indicating that Tcf12 and Notch1 operate in the same pathway. Finally, we identify a tumor suppressor gene set downstream of HEB, exhibiting significantly lower expression levels in pediatric T-ALL compared to B-ALL and brain cancer samples, the three most frequent pediatric cancers. In summary, our results indicate a tumor suppressor function of HEB/TCF12 in T-ALL to mitigate cell proliferation controlled by NOTCH1 in pre-leukemic stem cells and prevent NOTCH1-driven progression to T-ALL.

2022-03-24

Frontiers in Immunology (publié)

Vesicular trafficking is a key determinant of the statin response in acute myeloid leukemia

Jana K Krosl

Marie-Eve Bordeleau

Céline Moison

Tara MacRae

Isabel Boivin

Nadine Mayotte

Deanne Gracias

Irène Baccelli

Vincent-Philippe Lavallee

Richard Bisaillon

Bernhard Lehnertz

Rodrigo Mendoza-Sanchez

Réjean Ruel

Thierry Bertomeu

Jasmin Coulombe-Huntington

Geneviève Boucher

Nandita Noronha

C. Pabst

M. Tyers

Patrick Gendron … (voir 5 de plus)

Frederic Barabe

Anne Marinier

Josée Hébert

Guy Sauvageau

Key Points Inhibition of RAB protein function mediates the anti–acute myeloid leukemia activity of statins. Statin sensitivity is associat… (voir plus)ed with enhanced vesicle-mediated traffic.

2021-11-03

Blood Advances (published)

Vesicular trafficking is a key determinant of the statin response in acute myeloid leukemia

Jana Krosl

Marie-Eve Bordeleau

Céline Moison

Tara MacRae

Isabel Boivin

Nadine Mayotte

Deanne Gracias

Irène Baccelli

Vincent-Philippe Lavallee

Richard Bisaillon

Bernhard Lehnertz

Rodrigo Mendoza-Sanchez

Réjean Ruel

Thierry Bertomeu

Jasmin Coulombe-Huntington

Geneviève Boucher

Nandita Noronha

Caroline Pabst

Mike Tyers

Patrick Gendron … (voir 5 de plus)

Frederic Barabe

Anne Marinier

Josée Hébert

Guy Sauvageau

Key Points Inhibition of RAB protein function mediates the anti–acute myeloid leukemia activity of statins. Statin sensitivity is associat… (voir plus)ed with enhanced vesicle-mediated traffic.

2021-11-03

Blood Advances (publié)

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

Tariq Daouda

Maude Dumont-Lagacé

Albert Feghaly

Yahya Benslimane

Rébecca Panes

Mathieu Courcelles

Mohamed Benhammadi

Lea Harrington

Pierre Thibault

François Major

Étienne Gagnon

Claude Perreault

MHC-I associated peptides (MAPs) play a central role in the elimination of virus-infected and neoplastic cells by CD8 T cells. However, accu… (voir plus)rately 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 increaser 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. Author summary MHC-I associated peptides (MAPs) are small fragments of intracellular proteins presented at the surface of cells and used by the immune system to detect and eliminate cancerous or virus-infected cells. While it is theoretically possible to predict which portions of the intracellular proteins will be naturally processed by the cells to ultimately reach the surface, current methodologies have prohibitively high false discovery rates. Here we introduce an artificial neural network called Codon Arrangement MAP Predictor (CAMAP) which integrates information from mRNA-to-protein translation to other factors regulating MAP biogenesis (e.g. MAP ligand score and transcript expression levels) to improve MAP prediction accuracy. While most MAP predictive approaches focus on MAP sequences per se, CAMAP’s novelty is to analyze the MAP-flanking mRNA sequences, thereby providing completely independent information for MAP prediction. We show on several datasets that the integration of CAMAP scores with other known factors involved in MAP presentation (i.e. MAP ligand score and mRNA expression) significantly improves MAP prediction accuracy, and further validate CAMAP learned features using an in-vitro assay. These findings may have major implications for the design of vaccines against cancers and viruses, and in times of pandemics could accelerate the identification of relevant MAPs of viral origins.

2021-10-22

PLoS Computational Biology (publié)

CAMAP: Artificial neural networks unveil the role of 1 codon arrangement in modulating MHC-I peptides 2 presentation

Tariq Daouda

Maude Dumont-Lagacé

Albert Feghaly

Yahya Benslimane

6. Rébecca

Panes

Mathieu Courcelles

Mohamed Benhammadi

Lea Harrington

Pierre Thibault

François Major

Étienne Gagnon

Claude Perreault

30 MHC-I associated peptides (MAPs) play a central role in the elimination of virus-infected and 31 neoplastic cells by CD8 T cells. However… (voir plus), accurately predicting the MAP repertoire remains 32 difficult, because only a fraction of the transcriptome generates MAPs. In this study, we 33 investigated whether codon arrangement (usage and placement) regulates MAP biogenesis. We 34 developed an artificial neural network called Codon Arrangement MAP Predictor (CAMAP), 35 predicting MAP presentation solely from mRNA sequences flanking the MAP-coding codons 36 (MCCs), while excluding the MCC per se . CAMAP predictions were significantly more accurate 37 when using original codon sequences than shuffled codon sequences which reflect amino acid 38 usage. Furthermore, predictions were independent of mRNA expression and MAP binding affinity 39 to MHC-I molecules and applied to several cell types and species. Combining MAP ligand scores, 40 transcript expression level and CAMAP scores was particularly useful to increaser MAP prediction 41 accuracy. Using an in vitro assay, we showed that varying the synonymous codons in the regions 42 flanking the MCCs (without changing the amino acid sequence) resulted in significant modulation 43 of MAP presentation at the cell surface. Taken together, our results demonstrate the role of codon 44 arrangement in the regulation of MAP presentation and support integration of both translational 45 and post-translational events in predictive algorithms to ameliorate modeling of the 46 immunopeptidome. 47 48 49 they modulated the levels of SIINFEKL presentation in both constructs, but enhanced translation efficiency could only be detected for OVA-RP. These data show that codon arrangement can modulate MAP presentation strength without any changes in the amino

CAMAP: Artificial neural networks unveil the role of 1 codon arrangement in modulating MHC-I peptides 2 presentation discovery of minor histocompatibility with

Tariq Daouda

Maude Dumont-Lagacé

Albert Feghaly

Yahya Benslimane

6. Rébecca

Panes

Mathieu Courcelles

Mohamed Benhammadi

Lea Harrington

Pierre Thibault

François Major

Étienne Gagnon

Claude Perreault

30 MHC-I associated peptides (MAPs) play a central role in the elimination of virus-infected and 31 neoplastic cells by CD8 T cells. However… (voir plus), accurately predicting the MAP repertoire remains 32 difficult, because only a fraction of the transcriptome generates MAPs. In this study, we 33 investigated whether codon arrangement (usage and placement) regulates MAP biogenesis. We 34 developed an artificial neural network called Codon Arrangement MAP Predictor (CAMAP), 35 predicting MAP presentation solely from mRNA sequences flanking the MAP-coding codons 36 (MCCs), while excluding the MCC per se . CAMAP predictions were significantly more accurate 37 when using original codon sequences than shuffled codon sequences which reflect amino acid 38 usage. Furthermore, predictions were independent of mRNA expression and MAP binding affinity 39 to MHC-I molecules and applied to several cell types and species. Combining MAP ligand scores, 40 transcript expression level and CAMAP scores was particularly useful to increaser MAP prediction 41 accuracy. Using an in vitro assay, we showed that varying the synonymous codons in the regions 42 flanking the MCCs (without changing the amino acid sequence) resulted in significant modulation 43 of MAP presentation at the cell surface. Taken together, our results demonstrate the role of codon 44 arrangement in the regulation of MAP presentation and support integration of both translational 45 and post-translational events in predictive algorithms to ameliorate modeling of the 46 immunopeptidome. 47 48 49 they modulated the levels of SIINFEKL presentation in both constructs, but enhanced translation efficiency could only be detected for OVA-RP. These data show that codon arrangement can modulate MAP presentation strength without any changes in the amino

Factorized embeddings learns rich and biologically meaningful embedding spaces using factorized tensor decomposition

Assya Trofimov

Joseph Paul Cohen

Claude Perreault

2020-07-01

Bioinform. (publié)