The neuropeptide receptor calcitonin receptor-like (CALCRL) is a potential therapeutic target in acute myeloid leukemia.
Linus Angenendt, Eike Bormann, Caroline Pabst, Vijay Alla, Dennis Görlich, Leonie Braun, Kim Dohlich, Christian Schwöppe, Stefan K Bohlander, Maria Francisca Arteaga, Klaus Wethmar, Wolfgang Hartmann, Adrian Angenendt, Torsten Kessler, Rolf M Mesters, Matthias Stelljes, Maja Rothenberg-Thurley, Karsten Spiekermann, Josée Hébert, Guy Sauvageau, Peter J M Valk, Bob Löwenberg, Hubert Serve, Carsten Müller-Tidow, Georg Lenz, Bernhard J Wörmann, M Christina Sauerland, Wolfgang Hiddemann, Wolfgang E Berdel, Utz Krug, Klaus H Metzeler, Jan-Henrik Mikesch, Tobias Herold, Christoph Schliemann
Leukemia 2019 DecCalcitonin 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.
Citation
Linus Angenendt, Eike Bormann, Caroline Pabst, Vijay Alla, Dennis Görlich, Leonie Braun, Kim Dohlich, Christian Schwöppe, Stefan K Bohlander, Maria Francisca Arteaga, Klaus Wethmar, Wolfgang Hartmann, Adrian Angenendt, Torsten Kessler, Rolf M Mesters, Matthias Stelljes, Maja Rothenberg-Thurley, Karsten Spiekermann, Josée Hébert, Guy Sauvageau, Peter J M Valk, Bob Löwenberg, Hubert Serve, Carsten Müller-Tidow, Georg Lenz, Bernhard J Wörmann, M Christina Sauerland, Wolfgang Hiddemann, Wolfgang E Berdel, Utz Krug, Klaus H Metzeler, Jan-Henrik Mikesch, Tobias Herold, Christoph Schliemann. The neuropeptide receptor calcitonin receptor-like (CALCRL) is a potential therapeutic target in acute myeloid leukemia. Leukemia. 2019 Dec;33(12):2830-2841
Mesh Tags
Substances
PMID: 31182782
View Full Text
