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Acute myeloid leukemia

The neuropeptide receptor calcitonin receptor-like (CALCRL) is a potential therapeutic target in acute myeloid leukemia

Leukemia volume 33, pages 2830–2841 (2019)Cite this article

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Abstract

Calcitonin receptor-like (CALCRL) is a G-protein-coupled neuropeptide receptor involved in the regulation of blood pressure, angiogenesis, cell proliferation, and apoptosis, and is currently emerging as a novel target for the treatment of migraine. This study characterizes the role of CALCRL in acute myeloid leukemia (AML). We analyzed CALCRL expression in collectively more than 1500 well-characterized AML patients from five international cohorts (AMLCG, HOVON, TCGA, Leucegene, and UKM) and evaluated associations with survival. In the AMLCG analytic cohort, increasing transcript levels of CALCRL were associated with decreasing complete remission rates (71.5%, 53.7%, 49.6% for low, intermediate, high CALCRL expression), 5-year overall (43.1%, 26.2%, 7.1%), and event-free survival (29.9%, 15.8%, 4.7%) (all P < 0.001). CALCRL levels remained associated with all endpoints on multivariable regression analyses. The prognostic impact was confirmed in all validation sets. Genes highly expressed in CALCRLhigh AML were significantly enriched in leukemic stem cell signatures and CALCRL levels were positively linked to the engraftment capacity of primary patient samples in immunocompromised mice. CRISPR-Cas9-mediated knockout of CALCRL significantly impaired colony formation in human myeloid leukemia cell lines. Overall, our study demonstrates that CALCRL predicts outcome beyond existing risk factors and is a potential therapeutic target in AML.

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Acknowledgements

This work is dedicated to the memory of Professor Thomas Büchner. We thank all patients and clinicians participating in the trials. The help of Irina Arnhold, Mirco Witte, and Hans-Joachim Schnittler with TMA staining and analysis is gratefully acknowledged. The statistical analysis was partially funded by the José Carreras Foundation (DJCLS H 09/01f to DG). The Leucegene project is 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, with supplementary funds from AmorChem. GS and JH are recipients of research chairs from the Canada Research Chair program and Industrielle-Alliance (Université de Montréal), respectively. The Banque de cellules leucémiques du Québec (BCLQ) is supported by grants from the Cancer Research Network of the Fonds de recherche du Québec-Santé. CP is supported by the German Cancer Aid (70111531). SKB is supported by Leukemia & Blood Cancer New Zealand and the family of Marijanna Kumerich. GL and WEB are supported by the German Research Foundation (DFG EXC 1003, Cluster of excellence “Cells in Motion”). TH and KS are supported by the Wilhelm Sander Foundation (2013.086.1 to TH and KS and 2013.086.2 to TH). TH is supported by the Physician Scientists Grant (G-509200-004) from the Helmholtz Zentrum München. C Schliemann and LA are supported by the Innovative Medical Research Fund of the University of Münster Medical School (SC211008 to CS and AN111813 to LA).

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Author notes

  1. These authors contributed equally: Linus Angenendt, Eike Bormann

  2. These authors contributed equally: Tobias Herold, Christoph Schliemann

Authors and Affiliations

  1. Department of Medicine A, University Hospital Münster, Münster, Germany

    Linus Angenendt, Vijay Alla, Leonie Braun, Kim Dohlich, Christian Schwöppe, Maria Francisca Arteaga, Klaus Wethmar, Torsten Kessler, Rolf M. Mesters, Matthias Stelljes, Georg Lenz, Wolfgang E. Berdel, Jan-Henrik Mikesch & Christoph Schliemann

  2. Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany

    Eike Bormann, Dennis Görlich & M. Christina Sauerland

  3. Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany

    Caroline Pabst & Carsten Müller-Tidow

  4. Leukaemia & Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

    Stefan K. Bohlander

  5. Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany

    Wolfgang Hartmann

  6. Department of Biophysics, Faculty of Medicine, Centre for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, Homburg, Germany

    Adrian Angenendt

  7. Department of Medicine III, University Hospital Grosshadern, LMU Munich, Munich, Germany

    Maja Rothenberg-Thurley, Karsten Spiekermann, Wolfgang Hiddemann, Klaus H. Metzeler & Tobias Herold

  8. The Leucegene Project at Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada

    Josée Hébert & Guy Sauvageau

  9. Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada

    Josée Hébert & Guy Sauvageau

  10. Quebec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada

    Josée Hébert & Guy Sauvageau

  11. Department of Medicine, University of Montreal, Montreal, QC, Canada

    Josée Hébert & Guy Sauvageau

  12. Department of Hematology, Erasmus University Medical Centre, Rotterdam, The Netherlands

    Peter J. M. Valk & Bob Löwenberg

  13. Department of Hematology and Oncology, University Hospital Frankfurt, Frankfurt, Germany

    Hubert Serve

  14. Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Campus Virchow, Berlin, Germany

    Bernhard J. Wörmann

  15. Department of Medicine 3, Klinikum Leverkusen, Leverkusen, Germany

    Utz Krug

  16. Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Center for Environmental Health (HMGU), Munich, Germany

    Tobias Herold

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  1. Linus Angenendt
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Contributions

LA, EB, TH and C Schliemann designed the study. LA, MCS, DG, AA, UK, KHM, C Schliemann, and EB performed statistical studies and analyzed the data. KW, TK, RMM, MS, HS and GL contributed to data analysis. KHM, SKB, MR-T, KS, W Hiddemann, and TH provided expression and mutational data on the AMLCG cohort. MCS, BJW, W Hiddemann, and WEB coordinated the AMLCG99 trial. JH, GS, PJMV and BL provided expression data and clinical annotations for validation cohorts. LA, LB, KD, C Schwöppe, W Hartmann, and C Schliemann characterized the UKM cohort and performed TMA stainings. CP and CMT provided expression data in hematopoietic subsets and in vivo engraftment experiments. VA, MFA and J-HM performed the CRISPR-Cas9 experiments. C Schliemann and LA wrote the manuscript. All authors interpreted the data and made the decision to submit the manuscript for publication.

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Correspondence to Linus Angenendt, Tobias Herold or Christoph Schliemann.

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Angenendt, L., Bormann, E., Pabst, C. et al. The neuropeptide receptor calcitonin receptor-like (CALCRL) is a potential therapeutic target in acute myeloid leukemia. Leukemia 33, 2830–2841 (2019). https://doi.org/10.1038/s41375-019-0505-x

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