Unmasking the dynamic influence of the hematopoietic niche as an oncogenic path to myeloid neoplasms evolution

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.

Large-Scale 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 leukemic transformation of “pre-leukemic” clonal myeloid conditions.

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.

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 re-establishing healthy hematopoietic stem cells' 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.