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:10.1101/2020.08.17.253542

Cited by 4 publications

(5 citation statements)

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“…In hematological malignancies, it has been extensively demonstrated that, interfering with CSC biology, sensitizes tumors to chemotherapy. A recent paper identified calcitonin receptor-like receptor (CALCRL) is highly expressed in leukemia DTPs and its depletion reduces leukemia stem cell frequency after chemotherapy [ 16 ]. Consistent with this notion, cancers with high expression of stemness gene signatures are associated with poor prognosis [ 17 , 18 ]…”

Section: What Are the Characteristics Of Drug-tolerant Cells?mentioning

confidence: 99%

Fighting Drug Resistance through the Targeting of Drug-Tolerant Persister Cells

Conti

Dias

Bernards

2021

Cancers

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Designing specific therapies for drug-resistant cancers is arguably the ultimate challenge in cancer therapy. While much emphasis has been put on the study of genetic alterations that give rise to drug resistance, much less is known about the non-genetic adaptation mechanisms that operate during the early stages of drug resistance development. Drug-tolerant persister cells have been suggested to be key players in this process. These cells are thought to have undergone non-genetic adaptations that enable survival in the presence of a drug, from which full-blown resistant cells may emerge. Such initial adaptations often involve engagement of stress response programs to maintain cancer cell viability. In this review, we discuss the nature of drug-tolerant cancer phenotypes, as well as the non-genetic adaptations involved. We also discuss how malignant cells employ homeostatic stress response pathways to mitigate the intrinsic costs of such adaptations. Lastly, we discuss which vulnerabilities are introduced by these adaptations and how these might be exploited therapeutically.

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Section: What Are the Characteristics Of Drug-tolerant Cells?mentioning

confidence: 99%

Fighting Drug Resistance through the Targeting of Drug-Tolerant Persister Cells

Conti

Dias

Bernards

2021

Cancers

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“…Angenendt et al found that knockdown of CALCRL significantly inhibited colony formation in human myeloid leukemia cell lines, suggesting that CALCRL may be a potential therapeutic target in AML (13). In addition, Larrue et al found that CALCRL depletion reduced the frequency of leukemic stem cells in relapse-initiating cells after in vivo chemotherapy (29). CALCRL plays a role in tumor progression by mediating CGRP and ADM.…”

Section: Discussionmentioning

confidence: 99%

Interfering with CALCRL expression inhibits glioma proliferation, promotes apoptosis, and predicts prognosis in low-grade gliomas

Gu¹,

Shu²,

Zhou³

et al. 2022

Ann Transl Med

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Background: CALCRL is involved in a variety of key biological processes, including cell proliferation, apoptosis, angiogenesis, and inflammation. However, the role of CALCRL in glioma remains unknown.The purpose of this study was to investigate the effect of differential CALCRL expression on the malignant progression of glioma and its value in glioma prognosis.Methods: Sequencing data from glioma and normal tissues were downloaded from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, and the downloaded data were statistically analyzed using bioinformatics tools and the corresponding R package. The expression of CALCRL in normal brain tissue and different grades of glioma tissue was detected by pathological and immunohistochemical staining of clinical glioma specimens. The expression of CALCRL in different glioma cell lines was detected by quantitative real-time polymerase chain reaction (qRT-PCR), and the U87 cell line with high expression was selected to construct the CALCRL knockdown model by transfection with short hairpin (shRNA). The cell proliferation ability was detected by Celigo assay and 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the ability of cell clone formation was detected by clone formation assay, and the level of apoptosis was detected by flow cytometry. Results:The expression of CALCRL in glioma was significantly upregulated compared with that of normal tissue, especially in low-grade glioma (LGG) compared to glioblastoma, and the differential expression of CALCRL correlated significantly with the prognosis of LGG. Clinical pathology and immunohistochemistry showed that the expression of CALCRL was related to the pathological grade of glioma, and the highest expression was found in World Health Organization (WHO) grade Ⅲ glioma. The results of qRT-PCR showed that CALCRL expression was highest in the U87 cell line. After knockdown of CALCRL expression, the proliferation and clonogenic ability of U87 cells were significantly decreased, and the apoptosis rate was significantly increased.Conclusions: CALCRL is highly expressed in LGG. Interfering with CALCRL expression inhibits glioma cell proliferation and promotes apoptosis, and thus has potential as a biomarker and therapeutic target for the prognosis of those with LGGs.

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“…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

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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.

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Adrenomedullin-CALCRL Axis Controls Relapse-Initiating Drug Tolerant Acute Myeloid Leukemia Cells

Cited by 4 publications

References 50 publications

Fighting Drug Resistance through the Targeting of Drug-Tolerant Persister Cells

Fighting Drug Resistance through the Targeting of Drug-Tolerant Persister Cells

Interfering with CALCRL expression inhibits glioma proliferation, promotes apoptosis, and predicts prognosis in low-grade gliomas

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

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