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

ABSTRACT 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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through

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BIOINFORMATICS ANALYSIS AND EXPERIMENTAL VALIDATION OF PDGFD AS A PROMISING DIAGNOSTIC BIOMARKER FOR ACUTE MYELOID LEUKEMIA Article Open access 28 April 2025 A HIGHLY HETEROGENEOUS

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leukemia. Thromb Res. 2015;135:588–93. Article  PubMed  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS 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. AUTHOR

INFORMATION AUTHORS AND AFFILIATIONS * The Leucegene project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, Canada Vincent-Philippe Lavallée, 

Jalila Chagraoui, Tara MacRae, Jana Krosl, Sébastien Lemieux, Anne Marinier, Caroline Pabst, Josée Hébert & Guy Sauvageau * Division of Hematology, Hôpital Maisonneuve-Rosemont,

Montréal, Canada Vincent-Philippe Lavallée, Sébastien Lemieux, Anne Marinier, Josée Hébert & Guy Sauvageau * Quebec Leukemia Cell Bank, Hôpital Maisonneuve-Rosemont, Montréal, Canada

Miriam Marquis, Sébastien Lemieux, Anne Marinier, Josée Hébert & Guy Sauvageau * Department of Medicine, Université de Montréal, Montréal, Canada Arnaud Bonnefoy, Sébastien Lemieux, Anne

Marinier, Georges-Étienne Rivard, Josée Hébert & Guy Sauvageau * Centre Hospitalier Universitaire Sainte-Justine, Montréal, Canada Arnaud Bonnefoy, Sébastien Lemieux, Anne Marinier 

& Georges-Étienne Rivard * Department of Computer Science and Operations Research, Université de Montréal, Montréal, Canada Sébastien Lemieux & Anne Marinier * Department of

Chemistry, Université de Montréal, Montréal, Canada Anne Marinier Authors * Vincent-Philippe Lavallée View author publications You can also search for this author inPubMed Google Scholar *

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CORRESPONDING AUTHORS Correspondence to Josée Hébert or Guy Sauvageau. ETHICS DECLARATIONS CONFLICT OF INTEREST The authors declare that they have no conflict of interest. ELECTRONIC

SUPPLEMENTARY MATERIAL SUPPLEMENTAL MATERIAL RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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).

https://doi.org/10.1038/s41375-018-0069-1 Download citation * Received: 22 October 2017 * Revised: 21 December 2017 * Accepted: 25 January 2018 * Published: 23 February 2018 * Issue Date:

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