HEIndividual fellowship2023–2024

StemLinc · Identification and characterization of long non-coding RNAs as drivers of stemness in hematopoietic stem cells and leukemia.

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2023-01-01 → 2024-12-31
EU contribution
€165,313
Participants
1
Scheme
HORIZON-TMA-MSCA-PF-EF

Lines connect the coordinator with its partners.

Results in brief

Identification and characterization of long non-coding RNAs as drivers of stemness in hematopoietic stem cells and leukemia.

Hematopoietic stem cells (HSCs) are a rare and essential population responsible for maintaining lifelong blood cell production. Their ability to self-renew and differentiate is crucial for sustaining a healthy blood and immune system. However, disruptions in these regulatory processes can result in hematological disorders, including leukemia. Understanding the molecular mechanisms that govern HSC identity and function is fundamental to uncovering how such dysregulations contribute to disease development. Long non-coding RNAs (lncRNAs) have emerged as key regulators of gene expression, yet their roles in HSC biology and leukemia remain largely unexplored. Unlike protein-coding RNAs, lncRNAs function as regulatory molecules, influencing gene activity and cellular behavior. Recent evidence suggests that lncRNAs play a crucial role in stem cell function, making them promising candidates for understanding hematopoiesis and developing novel therapeutic approaches for leukemia and other blood disorders. The StemLinc project, funded by the Marie Skłodowska-Curie Actions (MSCA) program, aimed to identify and characterize lncRNAs involved in the regulation of HSC stemness and their potential role in leukemia. The project’s specific objectives were: To generate a comprehensive catalog of hematopoietic lncRNAs through deep total RNA sequencing of primary mouse blood cells and bioinformatics analysis. To infer the function of identified lncRNAs using computational approaches integrating genomic, epigenomic and transcriptomic data. To validate the role of selected candidate lncRNAs through functional experiments and assess their relevance in leukemia. By integrating advanced transcriptomics, functional genomics, and computational analyses, StemLinc significantly advances multiple scientific domains: Hematopoietic system biology: Providing new insights into the transcriptional landscape of HSCs, progenitors, and differentiated blood cells. ncRNA biology: Characterizing previously unexplored lncRNAs, including mono-exonic transcripts, broadening the understanding of non-coding RNA regulation in hematopoiesis. Resource development for future research: Identifying candidate lncRNAs strongly associated with HSC identity and function, offering valuable insights for disease biomarker discovery and future large-scale studies.

Data: CORDIS, © European Union

Project objective

Hematopoietic stem cells (HSCs) are a unique population defined by their self-renewal capacity and the potential to give rise to all blood lineages. A complete understanding of the specific mechanisms controlling HSC self-renewal and multipotency is still lacking. This knowledge is fundamental to improve ex vivo HSC expansion with therapeutic purposes and to unveil the mechanisms that promote aberrant cellular growth in leukemia. Long non-coding RNAs (lncRNAs) are emerging as novel players of normal development and physiology and their dysregulation has been associated with multiple cancer types. Recent data suggests that lncRNAs may also act as molecular determinants of the balance between self-renewal and differentiation in HSCs. However, because of traditional limitations in RNA-profiling strategies, current lncRNA catalogs are still incomplete, representing likely only a fraction of the whole lncRNA repertoire expressed in cells. In this proposal, I aim to identify novel lncRNAs specifically involved in the regulation of HSC identity, to ultimately understand their function in normal hematopoiesis and leukemia. For this, I will construct a comprehensive HSC-specific lncRNA catalog through deep total-RNA sequencing of mouse HSCs and their closest cell descendants. I will then infer lncRNA functions through robust computational analyses and validate selected candidates in-vitro. Finally, I will investigate the role of HSC-specific lncRNAs in vivo, using a T-cell acute lymphoblastic leukemia mouse model. This work will extend our knowledge on lncRNAs, on the molecular mechanisms of HSC identity and on how their dysregulation leads to leukemia. By performing this project I will gain first-hand experience in normal and malignant hematopoiesis while reinforcing my expertise in lncRNA biology. I also expect to reach the highest levels of professional maturity and scientific independence which will allow me to establish a high-profile research group in the near future.

Original text from CORDIS.

Participants

  • FUNDACIO INSTITUT DE RECERCA CONTRA LA LEUCEMIA JOSEP CARRERAS · BadalonaCoordinatorSpain

Links

Data: CORDIS, © European Union