Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Acute myeloid leukemia

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

Leukemia volume 32, pages 1349–1357 (2018)Cite this article

Subjects

A Comment to this article was published on 23 March 2018

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando S, Iacobelli S, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. New Engl J Med. 2013;369:111–21.

    Article  PubMed  CAS  Google Scholar 

  2. Park JH, Qiao B, Panageas KS, Schymura MJ, Jurcic JG, Rosenblat TL, et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood. 2011;118:1248–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Lehmann S, Ravn A, Carlsson L, Antunovic P, Deneberg S, Möllgård L, et al. Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia. 2011;25:1128–34.

    Article  PubMed  CAS  Google Scholar 

  4. Tallman MS, Kim HT, Montesinos P, Appelbaum FR, de la Serna J, Bennett JM, et al. Does microgranular variant morphology of acute promyelocytic leukemia independently predict a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group. Blood. 2010;116:5650–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Rovelli A, Biondi A, Rajnoldi CA, Conter V, Giudici G, Jankovic M, et al. Microgranular variant of acute promyelocytic leukemia in children. J Clin Oncol. 1992;10:1413–8.

    Article  PubMed  CAS  Google Scholar 

  6. Mantha S, Tallman M, Soff GA. What’s new in the pathogenesis of the coagulopathy in acute promyelocytic leukemia?’. Curr Opin Hematol. 2016;23:121–6.

    Article  PubMed  CAS  Google Scholar 

  7. Kwaan HC, Cull EH. The coagulopathy in acute promyelocytic leukaemia—What have we learned in the past twenty years. Best Pract Res Clin Haematol. 2014;27:11–8.

    Article  PubMed  Google Scholar 

  8. Koyama T, Hirosawa S, Kawamata N, Tohda S, Aoki N. All-trans retinoic acid upregulates thrombomodulin and downregulates tissue-factor expression in acute promyelocytic leukemia cells: distinct expression of thrombomodulin and tissue factor in human leukemic cells. Blood. 1994;84:3001–9.

    PubMed  CAS  Google Scholar 

  9. Falanga A, Consonni R, Marchetti M, Locatelli G. Cancer procoagulant and tissue factor are differently modulated by all-trans-retinoic acid in acute promyelocytic leukemia cells. Blood. 1998;92:143–51.

    PubMed  CAS  Google Scholar 

  10. Menell JS, Cesarman GM, Jacovina AT, McLaughlin M, Lev EA, Hajjar KA. Annexin II and bleeding in acute promyelocytic leukemia. New Engl J Med. 1999;340:994–1004.

    Article  PubMed  CAS  Google Scholar 

  11. Liu Y, Wang Z, Jiang M, Dai L, Zhang W, Wu D, et al. The expression of annexin II and its role in the fibrinolytic activity in acute promyelocytic leukemia. Leuk Res. 2011;35:879–84.

    Article  PubMed  CAS  Google Scholar 

  12. Bennett B, Booth NA, Croll A. The bleeding disorder in acute promyelocytic leukaemia: fibrinolysis due to u‐PA rather than defibrination. Br J Haematol. 1989;71:511–7.

    Article  PubMed  CAS  Google Scholar 

  13. Dombret H, Scrobohaci M, Ghorra P, Zini J, Daniel M, Castaigne S, et al. Coagulation disorders associated with acute promyelocytic leukemia: corrective effect of all-trans retnoic acid treatment. Leukemia. 1993;7:2–9.

    PubMed  CAS  Google Scholar 

  14. Mantha S, Goldman DA, Devlin SM, Lee J-WW, Zannino D, Collins M, et al. Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era. Blood. 2017;129:1763–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Madan V, Shyamsunder P, Han L, Mayakonda A, Nagata Y, Sundaresan J, et al. Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia. Leukemia. 2016;30:1672–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. New Engl J Med. 2013;368:2059–74.

    Article  CAS  Google Scholar 

  17. Lavallee V-P, Baccelli I, Krosl J, Wilhelm B, Barabe F, Gendron P, et al. The transcriptomic landscape and directed chemical interrogation of MLL-rearranged acute myeloid leukemias. Nat Genet. 2015;47:1030–7.

    Article  PubMed  CAS  Google Scholar 

  18. Liu J-YY, Li N, Yang J, Li N, Qiu H, Ai D, et al. Metabolic profiling of murine plasma reveals an unexpected biomarker in rofecoxib-mediated cardiovascular events. Proc Natl Acad Sci USA. 2010;107:17017–22.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kroll MH, Biswas B, Budd JR, Durham P, Gorman RT, Gwise TE et al. Assessment of the diagnostic accuracy of laboratory tests using receiver operating characteristic curves; approved guideline-second edition. Clinical and Laboratory Standards Institute Document. 2011;31:1–45.

  20. Beitinjaneh A, Jang S, Roukoz H, Majhail NS. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations in acute promyelocytic leukemia: a systematic review. Leuk Res. 2010;34:831–6.

    Article  PubMed  CAS  Google Scholar 

  21. Chang Y-W, Hsieh P-W, Chang Y-T, Lu M-H, Huang T-F, Chong K-Y, et al. Identification of a novel platelet antagonist that binds to CLEC-2 and suppresses podoplanin-induced platelet aggregation and cancer metastasis. Oncotarget. 2015;6:42733–48.

    PubMed  PubMed Central  Google Scholar 

  22. Nakata M, Yada T, Soejima N, Maruyama I. Leptin promotes aggregation of human platelets via the long form of its receptor. Diabetes. 1999;48:426–9.

    Article  PubMed  CAS  Google Scholar 

  23. Schacht V, Ramirez MI, Hong Y-KK, Hirakawa S, Feng D, Harvey N, et al. T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J. 2003;22:3546–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Uhrin P, Zaujec J, Breuss JM, Olcaydu D, Chrenek P, Stockinger H, et al. Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation. Blood. 2010;115:3997–4005.

    Article  PubMed  CAS  Google Scholar 

  25. Suzuki-Inoue K, Kato Y, Inoue O, Kaneko MK, Mishima K, Yatomi Y, et al. Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells. J Biol Chem. 2007;282:25993–6001.

    Article  PubMed  CAS  Google Scholar 

  26. Riedl J, Preusser M, Mir Seyed Nazari P, Posch F, Panzer S, Marosi C, et al. Podoplanin expression in primary brain tumors induces platelet aggregation and increases risk of venous thromboembolism. Blood. 2017;129:1831–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Raica M, Cimpean AM, Ribatti D. The role of podoplanin in tumor progression and metastasis. Anticancer Res. 2008;28(5B):2997–3006.

    PubMed  Google Scholar 

  28. Rashidi A, Silverberg ML, Conkling PR, Fisher SI. Thrombosis in acute promyelocytic leukemia. Thromb Res. 2013;131:281–9.

    Article  PubMed  CAS  Google Scholar 

  29. Mitrovic M, Suvajdzic N, Elezovic I, Bogdanovic A, Djordjevic V, Miljic P, et al. Thrombotic events in acute promyelocytic 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

  1. 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

  2. Division of Hematology, Hôpital Maisonneuve-Rosemont, Montréal, Canada

    Vincent-Philippe Lavallée, Sébastien Lemieux, Anne Marinier, Josée Hébert & Guy Sauvageau

  3. Quebec Leukemia Cell Bank, Hôpital Maisonneuve-Rosemont, Montréal, Canada

    Miriam Marquis, Sébastien Lemieux, Anne Marinier, Josée Hébert & Guy Sauvageau

  4. Department of Medicine, Université de Montréal, Montréal, Canada

    Arnaud Bonnefoy, Sébastien Lemieux, Anne Marinier, Georges-Étienne Rivard, Josée Hébert & Guy Sauvageau

  5. Centre Hospitalier Universitaire Sainte-Justine, Montréal, Canada

    Arnaud Bonnefoy, Sébastien Lemieux, Anne Marinier & Georges-Étienne Rivard

  6. Department of Computer Science and Operations Research, Université de Montréal, Montréal, Canada

    Sébastien Lemieux & Anne Marinier

  7. Department of Chemistry, Université de Montréal, Montréal, Canada

    Anne Marinier

Authors
  1. Vincent-Philippe Lavallée
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jalila Chagraoui
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tara MacRae
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Miriam Marquis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arnaud Bonnefoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jana Krosl
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sébastien Lemieux
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anne Marinier
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Caroline Pabst
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Georges-Étienne Rivard
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Josée Hébert
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Guy Sauvageau
    View author publications

    You can also search for this author in PubMed Google Scholar

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

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:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-018-0069-1

This article is cited by

Search

Advanced search

Quick links