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Angenendt, L.* ; Bormann, E.* ; Pabst, C.* ; Alla, V.* ; Görlich, D.* ; Braun, L.* ; Dohlich, K.* ; Schwöppe, C.* ; Bohlander, S.K.* ; Arteaga, M.F.* ; Wethmar, K.* ; Hartmann, W.* ; Angenendt, A.* ; Kessler, T.* ; Mesters, R.M.* ; Stelljes, M.* ; Rothenberg-Thurley, M.* ; Spiekermann, K.* ; Hébert, J.* ; Sauvageau, G.* ; Valk, P.J.M.* ; Löwenberg, B.* ; Serve, H.* ; Müller-Tidow, C.* ; Lenz, G.* ; Wörmann, B.J.* ; Sauerland, M.C.* ; Hiddemann, W.* ; Berdel, W.E.* ; Krug, U.* ; Metzeler, K.H.* ; Mikesch, J.H.* ; Herold, T. ; Schliemann, C.

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

Leukemia 33, 2830-2841 (2019)
Verlagsversion Postprint DOI PMC
Open Access Green
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Gene-related Peptide; Bone-marrow; Baalc Expression; Tumor Xenograft; In-vitro; Adrenomedullin; Growth; Angiogenesis; Cancer; Stimulation
ISSN (print) / ISBN 0887-6924
e-ISSN 1476-5551
Zeitschrift Leukemia
Quellenangaben Band: 33, Heft: 12, Seiten: 2830-2841 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort Macmillan Building, 4 Crinan St, London N1 9xw, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)