ABSTRACT
BACKGROUND: Tumour dormancy, a resistance mechanism employed by cancer cells, is a significant challenge in cancer treatment, contributing to minimal residual disease (MRD) and potential relapse. Despite its clinical importance, the mechanisms underlying tumour dormancy and MRD remain unclear. In this study, we employed two syngeneic murine models of myeloid leukemia and melanoma to investigate the genetic, epigenetic, transcriptomic and protein signatures associated with tumour dormancy. We used a multiomics approach to elucidate the molecular mechanisms driving MRD and identify potential therapeutic targets. RESULTS: We conducted an in-depth omics analysis encompassing whole-exome sequencing (WES), copy number variation (CNV) analysis, chromatin immunoprecipitation followed by sequencing (ChIP-seq), transcriptome and proteome investigations. WES analysis revealed a modest overlap of gene mutations between melanoma and leukemia dormancy models, with a significant number of mutated genes found exclusively in dormant cells. These exclusive genetic signatures suggest selective pressure during MRD, potentially conferring resistance to the microenvironment or therapies. CNV, histone marks and transcriptomic gene expression signatures combined with Gene Ontology (GO) enrichment analysis highlighted the potential functional roles of the mutated genes, providing insights into the pathways associated with MRD. In addition, we compared "murine MRD genes" profiles to the corresponding human disease through public datasets and highlighted common features according to disease progression. Proteomic analysis combined with multi-omics genetic investigations, revealed a dysregulated proteins signature in dormant cells with minimal genetic mechanism involvement. Pathway enrichment analysis revealed the metabolic, differentiation and cytoskeletal remodeling processes involved in MRD. Finally, we identified 11 common proteins differentially expressed in dormant cells from both pathologies. CONCLUSIONS: Our study underscores the complexity of tumour dormancy, implicating both genetic and nongenetic factors. By comparing genomic, transcriptomic, proteomic, and epigenomic datasets, our study provides a comprehensive understanding of the molecular landscape of minimal residual disease. These results provide a robust foundation for forthcoming investigations and offer potential avenues for the advancement of targeted MRD therapies in leukemia and melanoma patients, emphasizing the importance of considering both genetic and nongenetic factors in treatment strategies.
Subject(s)
Disease Models, Animal , Melanoma , Neoplasm, Residual , Animals , Melanoma/genetics , Melanoma/pathology , Mice , Leukemia/genetics , Leukemia/pathology , DNA Copy Number Variations , Exome Sequencing , Mice, Inbred C57BL , Proteomics , Transcriptome , Gene Expression Profiling , MultiomicsABSTRACT
Acute myeloid leukemia (AML) is characterized by genetic aberrations in hematopoietic precursors of the myeloid lineage which lead to their defective maturation/function. While intensive chemotherapy protocols result in complete remission in 50 % to 80 % of AML patients, relapse occurs in the majority of cases. While calcium signalling is a well-known contributor to cancer hallmarks, few AML related studies have focused on relevant calcium targets. Our purpose here is to highlight calcium channels and associated signalling pathways involved in AML, in order to promote the development of treatments specifically targeting these pathways.
Title: LAM fatale ? - La signalisation calcique à la rescousse ! Abstract: La leucémie aiguë myéloïde (LAM) est une hémopathie maligne caractérisée par des aberrations génétiques de certains précurseurs hématopoïétiques de la lignée myéloïde qui entraînent un défaut de maturation et/ou de fonctionnement. Malgré une chimiothérapie intensive entraînant une rémission complète chez 50 à 80 % des patients, la rechute survient dans la majorité des cas. Bien que la signalisation calcique soit bien décrite dans les cancers solides, l'étude de cibles pertinentes dépendant du calcium a retenu peu d'attention dans la LAM jusqu'à aujourd'hui. L'objectif de cette revue est d'offrir une piste de réflexion sur l'identification de canaux calciques spécifiques et de voies de signalisation associées impliquées dans la LAM, et ainsi de promouvoir la recherche de nouvelles approches thérapeutiques efficaces ciblant spécifiquement ces voies.
Subject(s)
Calcium , Leukemia, Myeloid, Acute , Humans , Leukemia, Myeloid, Acute/genetics , Calcium Signaling , Calcium Channels , Antineoplastic Combined Chemotherapy ProtocolsABSTRACT
Acute myeloid leukemia (AML) is a hematological malignancy with a high risk of relapse. This issue is associated with the development of mechanisms leading to drug resistance that are not yet fully understood. In this context, we previously showed the clinical significance of the ATP binding cassette subfamily B-member 1 (ABCB1) in AML patients, namely its association with stemness markers and an overall worth prognosis. Calcium signaling dysregulations affect numerous cellular functions and are associated with the development of the hallmarks of cancer. However, in AML, calcium-dependent signaling pathways remain poorly investigated. With this study, we show the involvement of the ORAI1 calcium channel in store-operated calcium entry (SOCE), the main calcium entry pathway in non-excitable cells, in two representative human AML cell lines (KG1 and U937) and in primary cells isolated from patients. Moreover, our data suggest that in these models, SOCE varies according to the differentiation status, ABCB1 activity level and leukemic stem cell (LSC) proportion. Finally, we present evidence that ORAI1 expression and SOCE amplitude are modulated during the establishment of an apoptosis resistance phenotype elicited by the chemotherapeutic drug Ara-C. Our results therefore suggest ORAI1/SOCE as potential markers of AML progression and drug resistance apparition.
Subject(s)
Cytarabine , Leukemia, Myeloid, Acute , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/metabolism , Calcium/metabolism , Calcium Signaling , Cell Line , Cytarabine/metabolism , Humans , Leukemia, Myeloid, Acute/genetics , ORAI1 Protein/genetics , ORAI1 Protein/metabolism , Stromal Interaction Molecule 1/genetics , Stromal Interaction Molecule 1/metabolismABSTRACT
Acute myeloid leukemia (AML) is a clonal disorder characterized by genetic aberrations in myeloid primitive cells (blasts) which lead to their defective maturation/function and their proliferation in the bone marrow (BM) and blood of affected individuals. Current intensive chemotherapy protocols result in complete remission in 50% to 80% of AML patients depending on their age and the AML type involved. While alterations in calcium signaling have been extensively studied in solid tumors, little is known about the role of calcium in most hematologic malignancies, including AML. Our purpose with this review is to raise awareness about this issue and to present (i) the role of calcium signaling in AML cell proliferation and differentiation and in the quiescence of hematopoietic stem cells; (ii) the interplay between mitochondria, metabolism, and oxidative stress; (iii) the effect of the BM microenvironment on AML cell fate; and finally (iv) the mechanism by which chemotherapeutic treatments modify calcium homeostasis in AML cells.