PLASTicity of Endothelial Cell as new Target for acute myeloId leukemia TherapY

Introduction

Acute myeloid leukemias (AML) are aggressive blood cancers with poor overall prognosis. The main intervention line is high-dose chemotherapy, often associated with resistance, relapse, and long-term side effects. Although predominantly considered as genetic diseases of the hematopoietic system, AML also affects the bone marrow (BM) microenvironment, which contributes to disease pathogenesis.

Vascular Remodeling

Particularly, we have revealed a thorough remodeling of the vascular tree, with endothelial cells (ECs) displaying dismantled junctions and an embryonic-like molecular signature.

Research Hypothesis

Our research hypothesis is that these embryonic-like ECs (E-ECs) – displaying a high grade of plasticity – are progressively enriched during AML progression and foster a leukemia-reinforcing environment.

Objectives

Thus, this proposal aims at:

1. Deciphering the nature of enriched E-ECs in AML pathogenesis.
2. Identifying effective strategies to target them to improve therapeutic response.

Methodology

To this end, we will combine in vivo lineage tracing and OMIC studies in consolidated transplantable models of AML and patient-derived samples to:

• Decipher the molecular and clonal dynamics of BM ECs.
• Analyze their phenotypic plasticity toward regained Endothelial-to-Hematopoietic and Endothelial-to-Mesenchymal transition potential.

We will next explore novel therapeutic avenues by targeting microenvironmental plasticity in AML via candidate genes associated with the aforementioned phenotypes in vivo with engineered CRISPR-nanobodies.

Translation to Human System

Finally, this knowledge will be translated to the human system via pre-clinical validation of putative targets in a state-of-the-art human vascularized BM-on-chip platform.

Conclusion

In conclusion, this research proposal will uncover essential molecular mechanisms regulating stem cell niche dynamics in normal and pathological conditions, provide a thorough understanding of the molecular and cellular plasticity of BM ECs, and will result in innovative strategies to ameliorate AML clinical treatments.