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Leukemia. 2019 Jun 10. doi: 10.1038/s41375-019-0505-x. [Epub ahead of print]

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

Author information

1
Department of Medicine A, University Hospital Münster, Münster, Germany. linus.angenendt@ukmuenster.de.
2
Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany.
3
Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
4
Department of Medicine A, University Hospital Münster, Münster, Germany.
5
Leukaemia & Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.
6
Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany.
7
Department of Biophysics, Faculty of Medicine, Centre for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, Homburg, Germany.
8
Department of Medicine III, University Hospital Grosshadern, LMU Munich, Munich, Germany.
9
The Leucegene Project at Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada.
10
Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada.
11
Quebec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada.
12
Department of Medicine, University of Montreal, Montreal, QC, Canada.
13
Department of Hematology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
14
Department of Hematology and Oncology, University Hospital Frankfurt, Frankfurt, Germany.
15
Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Campus Virchow, Berlin, Germany.
16
Department of Medicine 3, Klinikum Leverkusen, Leverkusen, Germany.
17
Department of Medicine III, University Hospital Grosshadern, LMU Munich, Munich, Germany. tobias.herold@med.uni-muenchen.de.
18
Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Center for Environmental Health (HMGU), Munich, Germany. tobias.herold@med.uni-muenchen.de.
19
Department of Medicine A, University Hospital Münster, Münster, Germany. christoph.schliemann@ukmuenster.de.

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.

PMID:
31182782
DOI:
10.1038/s41375-019-0505-x

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