Publications by authors named "Vincent-Philippe Lavallée"

23 Publications

  • Page 1 of 1

High frequency of germline RUNX1 mutations in patients with RUNX1-mutated AML.

Blood 2020 05;135(21):1882-1886

The Leucegene Project at Institute for Research in Immunology and Cancer and.

RUNX1 is mutated in ∼10% of adult acute myeloid leukemia (AML). Although most RUNX1 mutations in this disease are believed to be acquired, they can also be germline. Indeed, germline RUNX1 mutations result in the well-described autosomal-dominant familial platelet disorder with predisposition to hematologic malignancies (RUNX1-FPD, FPD/AML, FPDMM); ∼44% of affected individuals progress to AML or myelodysplastic syndromes. Using the Leucegene RUNX1 AML patient group, we sought to investigate the proportion of germline vs acquired RUNX1 mutations in this cohort. Our results showed that 30% of RUNX1 mutations in our AML cohort are germline. Molecular profiling revealed higher frequencies of NRAS mutations and other mutations known to activate various signaling pathways in these patients with RUNX1 germline-mutated AML. Moreover, 2 patients (mother and son) had co-occurrence of RUNX1 and CEBPA germline mutations, with variable AML disease onset at 59 and 27 years, respectively. Together, these data suggest a higher than anticipated frequency of germline RUNX1 mutations in the Leucegene cohort and further highlight the importance of testing for RUNX1 mutations in instances in which allogeneic stem cell transplantation using a related donor is envisioned.
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http://dx.doi.org/10.1182/blood.2019003357DOI Listing
May 2020

Regenerative lineages and immune-mediated pruning in lung cancer metastasis.

Nat Med 2020 02 10;26(2):259-269. Epub 2020 Feb 10.

Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Developmental processes underlying normal tissue regeneration have been implicated in cancer, but the degree of their enactment during tumor progression and under the selective pressures of immune surveillance, remain unknown. Here we show that human primary lung adenocarcinomas are characterized by the emergence of regenerative cell types, typically seen in response to lung injury, and by striking infidelity among transcription factors specifying most alveolar and bronchial epithelial lineages. In contrast, metastases are enriched for key endoderm and lung-specifying transcription factors, SOX2 and SOX9, and recapitulate more primitive transcriptional programs spanning stem-like to regenerative pulmonary epithelial progenitor states. This developmental continuum mirrors the progressive stages of spontaneous outbreak from metastatic dormancy in a mouse model and exhibits SOX9-dependent resistance to natural killer cells. Loss of developmental stage-specific constraint in macrometastases triggered by natural killer cell depletion suggests a dynamic interplay between developmental plasticity and immune-mediated pruning during metastasis.
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http://dx.doi.org/10.1038/s41591-019-0750-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021003PMC
February 2020

Transcriptional Basis of Mouse and Human Dendritic Cell Heterogeneity.

Cell 2019 10 24;179(4):846-863.e24. Epub 2019 Oct 24.

Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Ludwig Center at Memorial Sloan Kettering Cancer Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Dendritic cells (DCs) play a critical role in orchestrating adaptive immune responses due to their unique ability to initiate T cell responses and direct their differentiation into effector lineages. Classical DCs have been divided into two subsets, cDC1 and cDC2, based on phenotypic markers and their distinct abilities to prime CD8 and CD4 T cells. While the transcriptional regulation of the cDC1 subset has been well characterized, cDC2 development and function remain poorly understood. By combining transcriptional and chromatin analyses with genetic reporter expression, we identified two principal cDC2 lineages defined by distinct developmental pathways and transcriptional regulators, including T-bet and RORγt, two key transcription factors known to define innate and adaptive lymphocyte subsets. These novel cDC2 lineages were characterized by distinct metabolic and functional programs. Extending our findings to humans revealed conserved DC heterogeneity and the presence of the newly defined cDC2 subsets in human cancer.
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http://dx.doi.org/10.1016/j.cell.2019.09.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838684PMC
October 2019

Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation.

Cell Stem Cell 2019 11 5;25(5):682-696.e8. Epub 2019 Sep 5.

Human Oncology and Pathogenesis Program and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Transcriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show that Stag2 deletion in hematopoietic stem and progenitor cells (HSPCs) results in altered hematopoietic function, increased self-renewal, and impaired differentiation. Chromatin immunoprecipitation (ChIP) sequencing revealed that, although Stag2 and Stag1 bind a shared set of genomic loci, a component of Stag2 binding sites is unoccupied by Stag1, even in Stag2-deficient HSPCs. Although concurrent loss of Stag2 and Stag1 abrogated hematopoiesis, Stag2 loss alone decreased chromatin accessibility and transcription of lineage-specification genes, including Ebf1 and Pax5, leading to increased self-renewal and reduced HSPC commitment to the B cell lineage. Our data illustrate a role for Stag2 in transformation and transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation.
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http://dx.doi.org/10.1016/j.stem.2019.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842438PMC
November 2019

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

Genetic characterization of ABT-199 sensitivity in human AML.

Leukemia 2020 01 12;34(1):63-74. Epub 2019 Jul 12.

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

Acute myeloid leukemias (AML) with mutations in the NPM1 gene (NPM1c+) represent a large AML subgroup with varying response to conventional treatment, highlighting the need to develop targeted therapeutic strategies for this disease. We screened a library of clinical drugs on a cohort of primary human AML specimens and identified the BCL2 inhibitor ABT-199 as a selective agent against NPM1c+ AML. Mutational analysis of ABT-199-sensitive and -resistant specimens identified mutations in NPM1, RAD21, and IDH1/IDH2 as predictors of ABT-199 sensitivity. Comparative transcriptome analysis further uncovered BCL2A1 as a potential mediator of ABT-199 resistance in AML. In line with our observation that RAD21 mutation confers sensitivity to ABT-199, we provide functional evidence that reducing RAD21 levels can sensitize AML cells to BCL2 inhibition. Moreover, we demonstrate that ABT-199 is able to produce selective anti-AML activity in vivo toward AML with mutations associated with compound sensitivity in PDX models. Overall, this study delineates the contribution of several genetic events to the response to ABT-199 and provides a rationale for the development of targeted therapies for NPM1c+ AML.
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http://dx.doi.org/10.1038/s41375-019-0485-xDOI Listing
January 2020

Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of OXPHOS Dependency in Acute Myeloid Leukemia.

Cancer Cell 2019 07;36(1):84-99.e8

The Leucegene Project at Institute for Research in Immunology (IRIC) and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Pavillon, Marcelle-Coutu, Montréal, QC H3T 1J4, Canada; Leukemia Cell Bank of Quebec, 5415 Assumption Boulevard, Montréal, QC H1T 2M4, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, 5415 Assumption Boulevard, Montréal, QC H1T 2M4, Canada; Department of Medicine, Université de Montréal, 2900 Boulevard Édouard-Montpetit, Montréal, QC H3T 1J4, Canada. Electronic address:

To identify therapeutic targets in acute myeloid leukemia (AML), we chemically interrogated 200 sequenced primary specimens. Mubritinib, a known ERBB2 inhibitor, elicited strong anti-leukemic effects in vitro and in vivo. In the context of AML, mubritinib functions through ubiquinone-dependent inhibition of electron transport chain (ETC) complex I activity. Resistance to mubritinib characterized normal CD34 hematopoietic cells and chemotherapy-sensitive AMLs, which displayed transcriptomic hallmarks of hypoxia. Conversely, sensitivity correlated with mitochondrial function-related gene expression levels and characterized a large subset of chemotherapy-resistant AMLs with oxidative phosphorylation (OXPHOS) hyperactivity. Altogether, our work thus identifies an ETC complex I inhibitor and reveals the genetic landscape of OXPHOS dependency in AML.
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http://dx.doi.org/10.1016/j.ccell.2019.06.003DOI Listing
July 2019

Hepatic leukemia factor is a novel leukemic stem cell regulator in DNMT3A, NPM1, and FLT3-ITD triple-mutated AML.

Blood 2019 07 10;134(3):263-276. Epub 2019 May 10.

Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.

, and are the most frequently mutated genes in cytogenetically normal acute myeloid leukemia (AML), but little is known about how these mutations synergize upon cooccurrence. Here we show that triple-mutated AML is characterized by high leukemia stem cell (LSC) frequency, an aberrant leukemia-specific CD34 immunophenotype, and synergistic upregulation of Hepatic Leukemia Factor (). Cell sorting based on the LSC marker GPR56 allowed isolation of triple-mutated from double-mutated subclones. Moreover, in R882-mutated patients, CpG hypomethylation at the transcription start site correlated with high mRNA expression, which was itself associated with poor survival. Loss of via CRISPR/Cas9 significantly reduced the CD34GPR56 LSC compartment of primary human triple-mutated AML cells in serial xenotransplantation assays. knockout cells were more actively cycling when freshly harvested from mice, but rapidly exhausted when reintroduced in culture. RNA sequencing of primary human triple-mutated AML cells after shRNA-mediated knockdown revealed the NOTCH target Hairy and Enhancer of Split 1 () and the cyclin-dependent kinase inhibitor as novel targets of HLF, potentially mediating these effects. Overall, our data establish as a novel LSC regulator in this genetically defined high-risk AML subgroup.
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http://dx.doi.org/10.1182/blood.2018862383DOI Listing
July 2019

Correction: High expression of HMGA2 independently predicts poor clinical outcomes in acute myeloid leukemia.

Blood Cancer J 2019 Feb 28;9(3):28. Epub 2019 Feb 28.

The Quebec Leukemia Cell Bank, Research Centre, Maisonneuve-Rosemont Hospital, Montréal, Canada.

Since the publication of the original article the authors noticed the the affiliation details for Paresh Vyas are incorrect. The correct affiliation details for this author are given below.
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http://dx.doi.org/10.1038/s41408-019-0190-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395678PMC
February 2019

Complex karyotype AML displays G2/M signature and hypersensitivity to PLK1 inhibition.

Blood Adv 2019 02;3(4):552-563

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

Patients diagnosed with acute myeloid leukemia with complex karyotype (CK AML) have an adverse prognosis using current therapies, especially when accompanied by alterations. We hereby report the RNA-sequencing analysis of the 68 CK AML samples included in the Leucegene 415 patient cohort. We confirm the frequent occurrence of alterations in this subgroup and further characterize the allele expression profile and transcript alterations of this gene. We also document that the RAS pathway (/, , , ) is frequently altered in this disease. Targeted chemical interrogation of genetically characterized primary CK AML samples identifies polo-like kinase 1 (PLK1) inhibitors as the most selective agents for this disease subgroup. status did not alter sensitivity to PLK1 inhibitors. Interestingly, CK AML specimens display a G2/M transcriptomic signature that includes higher expression levels of and correlates with PLK1 inhibition sensitivity. Together, our results highlight vulnerability in CK AML. In line with these in vitro data, volasertib shows a strong anti-AML activity in xenotransplantation mouse models of human adverse AML. Considering that PLK1 inhibitors are currently being investigated clinically in AML and myelodysplastic syndromes, our results provide a new rationale for PLK1-directed therapy in patients with adverse cytogenetic AML.
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http://dx.doi.org/10.1182/bloodadvances.2018028480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391664PMC
February 2019

Genetic mechanisms of primary chemotherapy resistance in pediatric acute myeloid leukemia.

Leukemia 2019 08 13;33(8):1934-1943. Epub 2019 Feb 13.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Acute myeloid leukemias (AML) are characterized by mutations of tumor suppressor and oncogenes, involving distinct genes in adults and children. While certain mutations have been associated with the increased risk of AML relapse, the genomic landscape of primary chemotherapy-resistant AML is not well defined. As part of the TARGET initiative, we performed whole-genome DNA and transcriptome RNA and miRNA sequencing analysis of pediatric AML with failure of induction chemotherapy. We identified at least three genetic groups of patients with induction failure, including those with NUP98 rearrangements, somatic mutations of WT1 in the absence of apparent NUP98 mutations, and additional recurrent variants including those in KMT2C and MLLT10. Comparison of specimens before and after chemotherapy revealed distinct and invariant gene expression programs. While exhibiting overt therapy resistance, these leukemias nonetheless showed diverse forms of clonal evolution upon chemotherapy exposure. This included selection for mutant alleles of FRMD8, DHX32, PIK3R1, SHANK3, MKLN1, as well as persistence of WT1 and TP53 mutant clones, and elimination of FLT3, PTPN11, and NRAS mutant clones. These findings delineate genetic mechanisms of primary chemotherapy resistance in pediatric AML, which should inform improved approaches for its diagnosis and therapy.
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http://dx.doi.org/10.1038/s41375-019-0402-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687545PMC
August 2019

High expression of HMGA2 independently predicts poor clinical outcomes in acute myeloid leukemia.

Blood Cancer J 2018 07 19;8(8):68. Epub 2018 Jul 19.

The Quebec Leukemia Cell Bank, Research Centre, Maisonneuve-Rosemont Hospital, Montréal, Canada.

In acute myeloid leukemia (AML), risk stratification based on cytogenetics and mutation profiling is essential but remains insufficient to select the optimal therapy. Accurate biomarkers are needed to improve prognostic assessment. We analyzed RNA sequencing and survival data of 430 AML patients and identified HMGA2 as a novel prognostic marker. We validated a quantitative PCR test to study the association of HMGA2 expression with clinical outcomes in 358 AML samples. In this training cohort, HMGA2 was highly expressed in 22.3% of AML, mostly in patients with intermediate or adverse cytogenetics. High expression levels of HMGA2 (H + ) were associated with a lower frequency of complete remission (58.8% vs 83.4%, P < 0.001), worse 3-year overall survival (OS, 13.2% vs 43.5%, P < 0.001) and relapse-free survival (RFS, 10.8% vs 44.2%, P < 0.001). A positive HMGA2 test also identified a subgroup of patients unresponsive to standard treatments. Multivariable analyses showed that H + was independently associated with significantly worse OS and RFS, including in the intermediate cytogenetic risk category. These associations were confirmed in a validation cohort of 260 patient samples from the UK NCRI AML17 trial. The HMGA2 test could be implemented in clinical trials developing novel therapeutic strategies for high-risk AML.
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http://dx.doi.org/10.1038/s41408-018-0103-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066481PMC
July 2018

Transcriptomic landscape of acute promyelocytic leukemia reveals aberrant surface expression of the platelet aggregation agonist Podoplanin.

Leukemia 2018 06 23;32(6):1349-1357. Epub 2018 Feb 23.

The Leucegene project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada.

Acute promyelocytic leukemia (APL) is a medical emergency because of associated lethal early bleeding, a condition preventable by prompt diagnosis and therapeutic intervention. The mechanisms underlying the hemostatic anomalies of APL are not completely elucidated. RNA-sequencing-based characterization of APL (n = 30) was performed and compared to that of other acute myeloid leukemia (n = 400) samples and normal promyelocytes. Perturbations in the transcriptome of coagulation and fibrinolysis-related genes in APL extend beyond known culprits and now include Thrombin, Factor X and Urokinase Receptor. Most intriguingly, the Podoplanin (PDPN) gene, involved in platelet aggregation, is aberrantly expressed in APL promyelocytes and is the most distinctive transcript for this disease. Using an antibody panel optimized for AML diagnosis by flow cytometry, we also found that PDPN was the most specific surface marker for APL, and that all-trans retinoic acid therapy rapidly decreases its expression. Functional studies showed that engineered overexpression of this gene in human leukemic cells causes aberrant platelet binding, activation and aggregation. PDPN-expressing primary APL cells, but not PDPN-negative primary leukemias, specifically induce platelet binding, activation and aggregation. Finally, PDPN expression on leukemia cells in a xenograft model was associated with thrombocytopenia and prolonged bleeding time in vivo. Together our results suggest that PDPN may contribute to the hemostatic perturbations found in APL.
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http://dx.doi.org/10.1038/s41375-018-0069-1DOI Listing
June 2018

MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia.

Cancer Discov 2018 04 5;8(4):478-497. Epub 2018 Feb 5.

Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.

In acute myeloid leukemia (AML), chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that knock-in mutant mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MEF2C phosphorylation was required for leukemia stem cell maintenance and induced by MARK kinases in cells. Treatment with the selective MARK/SIK inhibitor MRT199665 caused apoptosis and conferred chemosensitivity in MEF2C-activated human AML cell lines and primary patient specimens, but not those lacking MEF2C phosphorylation. These findings identify kinase-dependent dysregulation of transcription factor control as a determinant of therapy response in AML, with immediate potential for improved diagnosis and therapy for this disease. Functional proteomics identifies phosphorylation of MEF2C in the majority of primary chemotherapy-resistant AML. Kinase-dependent dysregulation of this transcription factor confers susceptibility to MARK/SIK kinase inhibition in preclinical models, substantiating its clinical investigation for improved diagnosis and therapy of AML. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-1271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882571PMC
April 2018

Chemogenomic Landscape of -mutated AML Reveals Importance of Allele Dosage in Genetics and Glucocorticoid Sensitivity.

Clin Cancer Res 2017 Nov 30;23(22):6969-6981. Epub 2017 Aug 30.

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

-mutated () acute myeloid leukemia (AML) is associated with adverse outcome, highlighting the urgent need for a better genetic characterization of this AML subgroup and for the design of efficient therapeutic strategies for this disease. Toward this goal, we further dissected the mutational spectrum and gene expression profile of AML and correlated these results to drug sensitivity to identify novel compounds targeting this AML subgroup. RNA-sequencing of 47 primary AML specimens was performed and sequencing results were compared to those of wild-type samples. Chemical screens were also conducted using specimens to identify compounds selectively affecting the viability of AML. We show that samples with no remaining wild-type allele are clinically and genetically distinct and display a more homogeneous gene expression profile. Chemical screening revealed that most specimens are sensitive to glucocorticoids (GCs) and we confirmed that GCs inhibit AML cell proliferation through their interaction with the glucocorticoid receptor (GR). We observed that specimens harboring mutations expected to result in low residual RUNX1 activity are most sensitive to GCs, and that coassociating mutations as well as GR levels contribute to GC sensitivity. Accordingly, acquired glucocorticoid sensitivity was achieved by negatively regulating expression in human AML cells. Our findings show the profound impact of allele dosage on gene expression profile and glucocorticoid sensitivity in AML, thereby opening opportunities for preclinical testing which may lead to drug repurposing and improved disease characterization. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1259DOI Listing
November 2017

mutations promote context-dependent transformation in acute myeloid leukemia with alterations.

Blood 2017 11 30;130(20):2204-2214. Epub 2017 Aug 30.

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

Neomorphic missense mutations affecting crucial lysine residues in histone H3 genes significantly contribute to a variety of solid cancers. Despite the high prevalence of mutations in pediatric glioblastoma and their well-established impact on global histone H3 lysine 27 di- and trimethylation (H3K27me2/3), the relevance of these mutations has not been studied in acute myeloid leukemia (AML). Here, we report the first identification of and mutations in patients with AML. We find that these lesions are major determinants of reduced H3K27me2/3 in these patients and that they are associated with common aberrations in the gene. We demonstrate that mutations are strong disease accelerators in a RUNX1-RUNX1T1 AML mouse model, suggesting that H3K27me2/3 has an important and selective leukemia-suppressive activity in this genetic context.
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http://dx.doi.org/10.1182/blood-2017-03-774653DOI Listing
November 2017

MiSTIC, an integrated platform for the analysis of heterogeneity in large tumour transcriptome datasets.

Nucleic Acids Res 2017 Jul;45(13):e122

The Leucegene project, Université de Montréal, Montréal, QC H3C 3J7, Canada.

Genome-wide transcriptome profiling has enabled non-supervised classification of tumours, revealing different sub-groups characterized by specific gene expression features. However, the biological significance of these subtypes remains for the most part unclear. We describe herein an interactive platform, Minimum Spanning Trees Inferred Clustering (MiSTIC), that integrates the direct visualization and comparison of the gene correlation structure between datasets, the analysis of the molecular causes underlying co-variations in gene expression in cancer samples, and the clinical annotation of tumour sets defined by the combined expression of selected biomarkers. We have used MiSTIC to highlight the roles of specific transcription factors in breast cancer subtype specification, to compare the aspects of tumour heterogeneity targeted by different prognostic signatures, and to highlight biomarker interactions in AML. A version of MiSTIC preloaded with datasets described herein can be accessed through a public web server (http://mistic.iric.ca); in addition, the MiSTIC software package can be obtained (github.com/iric-soft/MiSTIC) for local use with personalized datasets.
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http://dx.doi.org/10.1093/nar/gkx338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570030PMC
July 2017

Expression of immunoproteasome genes is regulated by cell-intrinsic and -extrinsic factors in human cancers.

Sci Rep 2016 Sep 23;6:34019. Epub 2016 Sep 23.

Institute for Research in Immunology and Cancer, Montreal, Quebec, Canada.

Based on transcriptomic analyses of thousands of samples from The Cancer Genome Atlas, we report that expression of constitutive proteasome (CP) genes (PSMB5, PSMB6, PSMB7) and immunoproteasome (IP) genes (PSMB8, PSMB9, PSMB10) is increased in most cancer types. In breast cancer, expression of IP genes was determined by the abundance of tumor infiltrating lymphocytes and high expression of IP genes was associated with longer survival. In contrast, IP upregulation in acute myeloid leukemia (AML) was a cell-intrinsic feature that was not associated with longer survival. Expression of IP genes in AML was IFN-independent, correlated with the methylation status of IP genes, and was particularly high in AML with an M5 phenotype and/or MLL rearrangement. Notably, PSMB8 inhibition led to accumulation of polyubiquitinated proteins and cell death in IP but not IP AML cells. Co-clustering analysis revealed that genes correlated with IP subunits in non-M5 AMLs were primarily implicated in immune processes. However, in M5 AML, IP genes were primarily co-regulated with genes involved in cell metabolism and proliferation, mitochondrial activity and stress responses. We conclude that M5 AML cells can upregulate IP genes in a cell-intrinsic manner in order to resist cell stress.
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http://dx.doi.org/10.1038/srep34019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034284PMC
September 2016

Chemo-genomic interrogation of CEBPA mutated AML reveals recurrent CSF3R mutations and subgroup sensitivity to JAK inhibitors.

Blood 2016 06 31;127(24):3054-61. Epub 2016 Mar 31.

The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada; Quebec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada; and Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.

In this study, we analyzed RNA-sequencing data of 14 samples characterized by biallelic CEBPA (CEBPA(bi)) mutations included in the Leucegene collection of 415 primary acute myeloid leukemia (AML) specimens, and describe for the first time high frequency recurrent mutations in the granulocyte colony-stimulating factor receptor gene CSF3R, which signals through JAK-STAT proteins. Chemical interrogation of these primary human specimens revealed a uniform and specific sensitivity to all JAK inhibitors tested irrespective of their CSF3R mutation status, indicating a general sensitization of JAK-STAT signaling in this leukemia subset. Altogether, these results identified the co-occurrence of mutations in CSF3R and CEBPA in a well-defined AML subset, which uniformly responds to JAK inhibitors and paves the way to personalized clinical trials for this disease.
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http://dx.doi.org/10.1182/blood-2016-03-705053DOI Listing
June 2016

RNA-sequencing analysis of core binding factor AML identifies recurrent ZBTB7A mutations and defines RUNX1-CBFA2T3 fusion signature.

Blood 2016 05 11;127(20):2498-501. Epub 2016 Mar 11.

The Leucegene project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada; Quebec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada; and Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.

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http://dx.doi.org/10.1182/blood-2016-03-703868DOI Listing
May 2016

GPR56 identifies primary human acute myeloid leukemia cells with high repopulating potential in vivo.

Blood 2016 Apr 1;127(16):2018-27. Epub 2016 Feb 1.

Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec, Centre de Recherche en Infectiologie du Centre Hospitalier de l'Université de Laval, Quebec City, QC, Canada; CHU de Québec Hôpital Enfant-Jésus, Quebec City, QC, Canada; and Department of Medicine, University Laval, Quebec City, QC, Canada.

Acute myeloid leukemia (AML) is a genetically heterogeneous hematologic malignancy, which is initiated and driven by a rare fraction of leukemia stem cells (LSCs). Despite the difficulties of identifying a common LSC phenotype, there is increasing evidence that high expression of stem cell gene signatures is associated with poor clinical outcome. Identification of functionally distinct subpopulations in this disease is therefore crucial to dissecting the molecular machinery underlying LSC self-renewal. Here, we combined next-generation sequencing technology with in vivo assessment of LSC frequencies and identified the adhesion G protein-coupled receptor 56 (GPR56) as a novel and stable marker for human LSCs for the majority of AML samples. High GPR56 expression was significantly associated with high-risk genetic subgroups and poor outcome. Analysis of GPR56 in combination with CD34 expression revealed engraftment potential of GPR56(+)cells in both the CD34(-)and CD34(+)fractions, thus defining a novel LSC compartment independent of the CD34(+)CD38(-)LSC phenotype.
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http://dx.doi.org/10.1182/blood-2015-11-683649DOI Listing
April 2016

The transcriptomic landscape and directed chemical interrogation of MLL-rearranged acute myeloid leukemias.

Nat Genet 2015 Sep 3;47(9):1030-7. Epub 2015 Aug 3.

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

Using next-generation sequencing of primary acute myeloid leukemia (AML) specimens, we identified to our knowledge the first unifying genetic network common to the two subgroups of KMT2A (MLL)-rearranged leukemia, namely having MLL fusions or partial tandem duplications. Within this network, we experimentally confirmed upregulation of the gene with the most subtype-specific increase in expression, LOC100289656, and identified cryptic MLL fusions, including a new MLL-ENAH fusion. We also identified a subset of MLL fusion specimens carrying mutations in SPI1 accompanied by inactivation of its transcriptional network, as well as frequent RAS pathway mutations, which sensitized the leukemias to synthetic lethal interactions between MEK and receptor tyrosine kinase inhibitors. This transcriptomics-based characterization and chemical interrogation of human MLL-rearranged AML was a valuable approach for identifying complementary features that define this disease.
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http://dx.doi.org/10.1038/ng.3371DOI Listing
September 2015

EVI1-rearranged acute myeloid leukemias are characterized by distinct molecular alterations.

Blood 2015 Jan 20;125(1):140-3. Epub 2014 Oct 20.

The Leucegene Project at the Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada; Division of Hematology, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada; Banque de Cellules Leucémiques du Québec, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada; and Department of Medicine, Faculty of Medicine, Université de Montréal, QC, Canada.

The genetic and transcriptional signature of EVI1 (ecotropic viral integration site 1)-rearranged (EVI1-r) acute myeloid leukemias (AMLs) remains poorly defined. We performed RNA sequencing of 12 EVI1-r AMLs and compared the results with those of other AML subtypes (n = 139) and normal CD34(+) cells (n = 17). Results confirm high frequencies of RAS and other activated signaling mutations (10/12 AMLs) and identify new recurrent mutations in splicing factors (5/12 AMLs in SF3B1 and 2/12 AMLs in U2AF1), IKZF1 (3/12 AMLs), and TP53 (3/12 AMLs). Mutations in IKZF1, a gene located on chromosome 7, and monosomy 7 are mutually exclusive in this disease. Moreover IKZF1 expression is halved in monosomy 7 leukemias. EVI-r AMLs are also characterized by a unique transcriptional signature with high expression levels of MECOM, PREX2, VIP, MYCT1, and PAWR. Our results suggest that EVI1-r AMLs could be molecularly defined by specific transcriptomic anomalies and a hitherto unseen mutational pattern. Larger patient cohorts will better determine the frequency of these events.
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Source
http://dx.doi.org/10.1182/blood-2014-07-591529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358966PMC
January 2015