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

被引：33

作者：

Angenendt, Linus ^{[1
]}

Bormann, Eike ^{[2
]}

Pabst, Caroline ^{[3
]}

Alla, Vijay ^{[1
]}

Goerlich, Dennis ^{[2
]}

Braun, Leonie ^{[1
]}

Dohlich, Kim ^{[1
]}

Schwoeppe, Christian ^{[1
]}

Bohlander, Stefan K. ^{[4
]}

Arteaga, Maria Francisca ^{[1
]}

Wethmar, Klaus ^{[1
]}

Hartmann, Wolfgang ^{[5
]}

Angenendt, Adrian ^{[6
]}

Kessler, Torsten ^{[1
]}

Mesters, Rolf M. ^{[1
]}

Stelljes, Matthias ^{[1
]}

Rothenberg-Thurley, Maja ^{[7
]}

Spiekermann, Karsten ^{[7
]}

Hebert, Josee ^{[8
,9
,10
,11
]}

Sauvageau, Guy ^{[8
,9
,10
,11
]}

Valk, Peter J. M. ^{[12
]}

Loewenberg, Bob ^{[12
]}

Serve, Hubert ^{[13
]}

Mueller-Tidow, Carsten ^{[3
]}

Lenz, Georg ^{[1
]}

Woermann, Bernhard J. ^{[14
]}

Sauerland, M. Christina ^{[2
]}

Hiddemann, Wolfgang ^{[7
]}

Berdel, Wolfgang E. ^{[1
]}

Krug, Utz ^{[15
]}

Metzeler, Klaus H. ^{[7
]}

Mikesch, Jan-Henrik ^{[1
]}

Herold, Tobias ^{[7
,16
]}

Schliemann, Christoph ^{[1
]}

机构：

[1] Univ Hosp Munster, Dept Med A, Munster, Germany

[2] Univ Munster, Inst Biostat & Clin Res, Munster, Germany

[3] Univ Hosp Heidelberg, Dept Med 5, Heidelberg, Germany

[4] Univ Auckland, Dept Mol Med & Pathol, Leukaemia & Blood Canc Res Unit, Auckland, New Zealand

[5] Univ Hosp Munster, Gerhard Domagk Inst Pathol, Munster, Germany

[6] Saarland Univ, CIPMM, Fac Med, Dept Biophys, Homburg, Germany

[7] Ludwig Maximilians Univ Munchen, Univ Hosp Grosshadern, Dept Med 3, Munich, Germany

[8] Univ Montreal, Inst Res Immunol & Canc, Leucegene Project, Montreal, PQ, Canada

[9] Maisonneuve Rosemont Hosp, Div Hematol Oncol, Montreal, PQ, Canada

[10] Maisonneuve Rosemont Hosp, Quebec Leukemia Cell Bank, Montreal, PQ, Canada

[11] Univ Montreal, Dept Med, Montreal, PQ, Canada

[12] Erasmus Univ, Med Ctr, Dept Hematol, Rotterdam, Netherlands

[13] Univ Hosp Frankfurt, Dept Hematol & Oncol, Frankfurt, Germany

[14] Charite, Dept Hematol Oncol & Tumor Immunol, Campus Virchow, Berlin, Germany

[15] Klinikum Leverkusen, Dept Med 3, Leverkusen, Germany

[16] German Ctr Environm Hlth HMGU, Helmholtz Zentrum Munchen, Res Unit Apoptosis Hematopoiet Stem Cells, Munich, Germany

来源：

LEUKEMIA | 2019年 / 33卷 / 12期

关键词：

GENE-RELATED PEPTIDE; BAALC EXPRESSION; TUMOR XENOGRAFT; BONE-MARROW; IN-VITRO; ADRENOMEDULLIN; GROWTH; ANGIOGENESIS; CANCER; STIMULATION;

D O I：

10.1038/s41375-019-0505-x

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：2830 / 2841

页数：12

共 52 条

[1]

[Anonymous], J PATHOL INFORM

[2] BAALC expression and FLT3 internal tandem duplication mutations in acute myeloid leukemia patients with normal cytogenetics:: Prognostic implications [J].