Adrenomedullin-CALCRL axis controls relapse-initiating drug tolerant acute myeloid leukemia cells

Larrue, Clément; Guiraud, Nathan; Mouchel, Pierre-Luc; Dubois, Marine; Farge, Thomas; Gotanègre, Mathilde; Bosc, Claudie; Saland, Estelle; Nicolau-Travers, Marie-Laure; Sabatier, Marie; Serhan, Nizar; Sahal, Ambrine; Boet, Emeline; Mouche, Sarah; Heydt, Quentin; Aroua, Nesrine; Stuani, Lucille; Kaoma, Tony; Angenendt, Linus; Mikesch, Jan‐Henrik; Schliemann, Christoph; Vergez, François; Tamburini, Jérôme; Récher, Christian; Sarry, Jean-Emmanuel

doi:10.1038/s41467-020-20717-9

Cited by 44 publications

(46 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 27,28 Interestingly, CALCRL has just been proposed as a master regulator of RICs in preclinical models of AML. 29 Although the association of CALCRL with OS and EFS has previously been shown for adult patients with AML, a direct association with the risk of relapse has not been described before, to the best of our knowledge. The clinical association of CALCRL expression with the risk of relapse in the pediatric AML population supports the biological role of CALCRL as a marker of stemness and a master regulator of RICs in human AML.…”

Section: Discussionmentioning

confidence: 72%

“…Recently, knockdown of CALCRL in human AML cell lines has been shown to prolong the survival of mice in AML xenotransplantation models and increase the sensitivity toward chemotherapy. 29 Further studies are necessary to determine the therapeutic efficacy of antibody- or small molecule-based inhibition of CALCRL and/or its ligands ADM and calcitonin gene-related peptide alone and in combination with chemotherapy in pediatric and adult AML.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Calcitonin receptor-like (CALCRL) is a marker of stemness and an independent predictor of outcome in pediatric AML

et al. 2021

Self Cite

View full text Add to dashboard Cite

We have recently identified the G protein-coupled neuropeptide receptor Calcitonin receptor-like (CALCRL) as an independent prognostic biomarker and a therapeutic target in more than 1500 adult patients with acute myeloid leukemia (AML). Here, we confirmed CALCRL expression as a prognostic factor in a cohort of 284 pediatric patients with AML. High CALCRL expression was independently associated with event free survival (EFS) (hazard ratio [HR], 1.87; 95% confidence interval [CI], 1.36-2.57; P=0.0001), overall survival (OS) (HR, 1.55; 95% [CI], 1.06-2.27; P=0.025) and cumulative incidence of relapse (CIR) (HR, 2.10; 95% CI, 1.49-1.96; P<0.0001) when adjusting for age, white blood cell count and genetic risk. Despite its association with leukemia stem cell (LSC) signatures, CALCRL expression remained associated with all endpoints when compared to the LSC17 score. The strong association of CALCRL expression with the risk of relapse also in the pediatric population supports its role as novel age-independent master regulator of relapse-initiating drug-tolerant AML cells in humans.

show abstract

Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Calcitonin receptor-like (CALCRL) is a marker of stemness and an independent predictor of outcome in pediatric AML

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…The prognosis model established in this study consisted of three inflammatory response-related genes (CALCRL, MMP14, and SELL), which were upregulated in LGG tumor tissues. The CALCRL gene codes the calcitonin receptor-like receptor which is a seven-transmembrane domain G-protein-coupled receptor (Larrue et al, 2021 andAngenendt et al, 2019). Its expression products are closely related to CALCRL and RAMP expressed on the cell surface by co-expression with three receptor active modification proteins (RAMPs).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Inflammatory Response–Related Genes, and Prognosis and Immune Infiltration in Patients With Low-Grade Glioma

Han

Zuo

et al. 2021

Front. Pharmacol.

View full text Add to dashboard Cite

Background: Although low-grade glioma (LGG) has a good prognosis, it is prone to malignant transformation into high-grade glioma. It has been confirmed that the characteristics of inflammatory factors and immune microenvironment are closely related to the occurrence and development of tumors. It is necessary to clarify the role of inflammatory genes and immune infiltration in LGG.Methods: We downloaded the transcriptome gene expression data and corresponding clinical data of LGG patients from the TCGA and GTEX databases to screen prognosis-related differentially expressed inflammatory genes with the difference analysis and single-factor Cox regression analysis. The prognostic risk model was constructed by LASSO Cox regression analysis, which enables us to compare the overall survival rate of high- and low-risk groups in the model by Kaplan–Meier analysis and subsequently draw the risk curve and survival status diagram. We analyzed the accuracy of the prediction model via ROC curves and performed GSEA enrichment analysis. The ssGSEA algorithm was used to calculate the score of immune cell infiltration and the activity of immune-related pathways. The CellMiner database was used to study drug sensitivity.Results: In this study, 3 genes (CALCRL, MMP14, and SELL) were selected from 9 prognosis-related differential inflammation genes through LASSO Cox regression analysis to construct a prognostic risk model. Further analysis showed that the risk score was negatively correlated with the prognosis, and the ROC curve showed that the accuracy of the model was better. The age, grade, and risk score can be used as independent prognostic factors (p < 0.001). GSEA analysis confirmed that 6 immune-related pathways were enriched in the high-risk group. We found that the degree of infiltration of 12 immune cell subpopulations and the scores of 13 immune functions and pathways in the high-risk group were significantly increased by applying the ssGSEA method (p < 0.05). Finally, we explored the relationship between the genes in the model and the susceptibility of drugs.Conclusion: This study analyzed the correlation between the inflammation-related risk model and the immune microenvironment. It is expected to provide a reference for the screening of LGG prognostic markers and the evaluation of immune response.

show abstract

“…In our analysis, none of the genes belonging to the ADM receptor complex (CALCRL, RAMP2, RAMP3) showed a correlation with endogenous ADM expression. However, it has been recently reported that CALCRL, the receptor of ADM and CGRP, is also overexpressed in LSC and its genomic ablation impaired the clonogenic capacity of AML cell lines (50) and the frequency of chemotherapy-resistant cells able to initiate leukemia relapse in preclinical models (81). In contrast to ADM, CALCRL was highly expressed in NPM1-mutated cases also carrying the FLT3-ITD (50).…”

Section: Discussionmentioning

confidence: 99%

Adrenomedullin Expression Characterizes Leukemia Stem Cells and Associates With an Inflammatory Signature in Acute Myeloid Leukemia

et al. 2021

View full text Add to dashboard Cite

Adrenomedullin (ADM) is a hypotensive and vasodilator peptide belonging to the calcitonin gene-related peptide family. It is secreted in vitro by endothelial cells and vascular smooth muscle cells, and is significantly upregulated by a number of stimuli. Moreover, ADM participates in the regulation of hematopoietic compartment, solid tumors and leukemias, such as acute myeloid leukemia (AML). To better characterize ADM involvement in AML pathogenesis, we investigated its expression during human hematopoiesis and in leukemic subsets, based on a morphological, cytogenetic and molecular characterization and in T cells from AML patients. In hematopoietic stem/progenitor cells and T lymphocytes from healthy subjects, ADM transcript was barely detectable. It was expressed at low levels by megakaryocytes and erythroblasts, while higher levels were measured in neutrophils, monocytes and plasma cells. Moreover, cells populating the hematopoietic niche, including mesenchymal stem cells, showed to express ADM. ADM was overexpressed in AML cells versus normal CD34+ cells and in the subset of leukemia compared with hematopoietic stem cells. In parallel, we detected a significant variation of ADM expression among cytogenetic subgroups, measuring the highest levels in inv(16)/t(16;16) or complex karyotype AML. According to the mutational status of AML-related genes, the analysis showed a lower expression of ADM in FLT3-ITD, NPM1-mutated AML and FLT3-ITD/NPM1-mutated cases compared with wild-type ones. Moreover, ADM expression had a negative impact on overall survival within the favorable risk class, while showing a potential positive impact within the subgroup receiving a not-intensive treatment. The expression of 135 genes involved in leukemogenesis, regulation of cell proliferation, ferroptosis, protection from apoptosis, HIF-1α signaling, JAK-STAT pathway, immune and inflammatory responses was correlated with ADM levels in the bone marrow cells of at least two AML cohorts. Moreover, ADM was upregulated in CD4+ T and CD8+ T cells from AML patients compared with healthy controls and some ADM co-expressed genes participate in a signature of immune tolerance that characterizes CD4+ T cells from leukemic patients. Overall, our study shows that ADM expression in AML associates with a stem cell phenotype, inflammatory signatures and genes related to immunosuppression, all factors that contribute to therapy resistance and disease relapse.

show abstract

Adrenomedullin-CALCRL axis controls relapse-initiating drug tolerant acute myeloid leukemia cells

Cited by 44 publications

References 63 publications

Calcitonin receptor-like (CALCRL) is a marker of stemness and an independent predictor of outcome in pediatric AML

Calcitonin receptor-like (CALCRL) is a marker of stemness and an independent predictor of outcome in pediatric AML

Comprehensive Analysis of Inflammatory Response–Related Genes, and Prognosis and Immune Infiltration in Patients With Low-Grade Glioma

Adrenomedullin Expression Characterizes Leukemia Stem Cells and Associates With an Inflammatory Signature in Acute Myeloid Leukemia

Contact Info

Product

Resources

About