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Acute myeloid leukemia

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


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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This work was supported by the Government of Canada through Genome Canada and the Ministère de l’économie, de l’innovation et des exportations du Québec through Génome Québec. Support from Canadian Cancer Society Research Institute and from the Leukemia and Lymphoma Society of Canada to GS is also acknowledged. The authors wish to thank Muriel Draoui for project coordination, Marie-Ève Bordeleau for insightful discussions, Sophie Corneau for sample coordination and Isabel Boivin for technical validations, as well as Marianne Arteau and Raphaëlle Lambert at the IRIC genomics platform for RNA sequencing. The collaboration of BCLQ coinvestigators and the dedicated work of BCLQ staff namely Giovanni D’Angelo, Claude Rondeau, Cyrielle Beaubois, and Sylvie Lavallée are also acknowledged. We also acknowledge Mélanie Fréchette and Koryne Léveillé for assistance with xenotransplantation experiments, N. Mayotte for technical assistance with mouse analyses and Danielle Gagné and Gaël Dulude for technical assistance with high-throughput flow cytometry. GS and JH are recipients of research chairs from the Canada Research Chair program and Industrielle-Alliance (Université de Montréal), respectively. BCLQ is supported by grants from the Cancer Research Network of the Fonds de recherche du Québec–Santé. RNA-Seq read mapping and transcript quantification were performed on the supercomputer Briaree from Université de Montréal, managed by Calcul Québec and Compute Canada. The operation of this supercomputer is funded by the Canada Foundation for Innovation (CFI), NanoQuébec, RMGA and the Fonds de recherche du Québec—Nature et technologies (FRQ-NT). VPL is supported by a fellowship from the Cole Foundation and by a Vanier Canada Graduate Scholarship.

Authors contributions

VPL contributed to project conception and coordination, analyzed genomic data, contributed to functional studies, generated figures, tables, and supplementary material, and was the main author of this paper. GS contributed to project conception and coordination and co-wrote the paper. JH contributed to project conception, analyzed the cytogenetic and FISH studies, and provided all AML samples and clinical data. JC performed flow cytometry analyses. TM generated cell line models and performed in vitro analyses with JC. MM performed and analyzed the flow cytometry analyses of primary specimens and generated corresponding material. JK performed in vitro chemical screen. SL was responsible for supervision of the bioinformatics team and of statistical analyses. AM is responsible for the chemistry team as part of the Leucegene project. CP processed and sequenced normal peripheral and bone marrow populations. AB performed platelet aggregation studies. GER supervised platelet aggregation studies and contributed to project conception. All authors have revised the manuscript.

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Correspondence to Josée Hébert or Guy Sauvageau.

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Lavallée, VP., Chagraoui, J., MacRae, T. et al. Transcriptomic landscape of acute promyelocytic leukemia reveals aberrant surface expression of the platelet aggregation agonist Podoplanin. Leukemia 32, 1349–1357 (2018).

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