Unmasking the dynamic influence of the hematopoietic niche as an oncogenic path to myeloid neoplasms evolution
This project aims to explore hematopoietic-niche interactions across myeloid neoplasm stages to develop innovative therapies that prevent acute myeloid leukemia and improve patient outcomes.
Projectdetails
Introduction
Although oncogenic driver mutations are found in healthy tissues sometimes at a prenatal stage, they do not often result in overt cancer. This genotype-phenotype discrepancy warrants the search for extrinsic mechanisms of cancer development and maintenance, such as aging or exposure to specific environments.
Research Objective
Using myeloid neoplasms as a cancer model, I aim to dissect the hematopoietic-niche partnership at the “pre-leukemic,” “leukemic,” and “post-leukemic” stages to identify innovative therapeutic strategies to prevent acute myeloid leukemia (AML) development, maintenance, and recurrence.
Methodology
To enable experimental modeling of the bone marrow niche at different disease stages, I collected longitudinal paired stromal and hematopoietic primary patient samples and generated physiologically relevant in vitro and in vivo humanized models.
Part 1: Genetic Screening
In this proposal, I will first apply large-scale pooled genetic screening approaches to gain insights into the role of the hematopoietic-niche cellular communication processes in the leukemic transformation of “pre-leukemic” clonal myeloid conditions.
Part 2: Spatial Single-Cell RNA Sequencing
In the second part of the proposal, I will combine cutting-edge spatial single-cell RNA sequencing technologies with functional genetic screening to dissect the “leukemic-niche” crosstalk and ultimately fuel the development of concomitant “seeds” and “soil” therapeutic strategies.
Part 3: Functional Single-Cell Screening
Finally, I will design a functional single-cell screening approach allowing modulation of the “post-leukemic” niche, to open the road for novel maintenance treatment strategies that re-establish healthy hematopoietic stem cell fitness advantage to prevent relapse.
Conclusion
Overall, the proposed research project provides a framework for defining and understanding the dynamic influence of the hematopoietic niche as an oncogenic path to myeloid neoplasms evolution. It represents a key step towards therapeutic niche reprogramming from a “malignant” to a “healthy” state, to improve cancer patients’ prognosis.
Financiële details & Tijdlijn
Financiële details
Subsidiebedrag | € 1.911.428 |
Totale projectbegroting | € 1.911.428 |
Tijdlijn
Startdatum | 1-1-2024 |
Einddatum | 31-12-2028 |
Subsidiejaar | 2024 |
Partners & Locaties
Projectpartners
- UNIVERSITE PARIS CITEpenvoerder
Land(en)
Vergelijkbare projecten binnen European Research Council
Project | Regeling | Bedrag | Jaar | Actie |
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Mechanistic models of leukemia-niche interaction using multimodal single cell profiling
This project aims to uncover AML's interactions with the bone marrow niche through advanced single-cell sequencing and modeling, potentially transforming treatment strategies for hematological malignancies.
Elucidating the Spatial and Temporal Dynamics of Acute Myeloid Leukemia Progression Using Functional Omics and High-Throughput In Vivo Screening
This project aims to explore the spatial and temporal dynamics of tumor progression in Acute Myeloid Leukemia to identify critical factors influencing cancer pathogenicity and potential therapeutic targets.
PLASTicity of Endothelial Cell as new Target for acute myeloId leukemia TherapY
This project aims to investigate embryonic-like endothelial cells in acute myeloid leukemia to identify therapeutic targets that enhance treatment responses and improve patient outcomes.
Understanding Diagnosing and Early intervention in the Myeloid malignancy Continuum
The Shlush lab aims to improve early diagnosis and treatment of myeloid malignancies by developing advanced diagnostic tools, exploring preleukemic mutations, and identifying targeted therapies.
Applying novel single-cell multiomics to elucidate leukaemia cell plasticity in resistance to targeted therapy
This project aims to develop a single-cell multiomics method to understand epigenetic resistance mechanisms in AML, enhancing treatment strategies against drug resistance.