7A. The osteochondral niche: how acute lymphoblastic leukaemia cells reshape skeletal stem cell differentiation to create a supportive and protective niche?

Interaction between leukemic cells and the bone marrow microenvironment are considered critical for leukemogenesis (Baryawno, N. et al. Cell, 2019). Leukemic blasts communicate with neighboring cells to reprogram their microenvironment and survive chemotherapy. Hence, targeting the tumor-supportive microenvironment holds the potential of increasing therapy efficacy; yet it is hampered by an incomplete definition of the niche composition and its communication network with the leukemic blasts.

Bone marrow skeletal cells are a major component of the niche, regulating hematopoiesis and skeletal regeneration. They are formed by a diverse landscape of cells, including mesenchymal stromal cells, osteochondral progenitors and their progeny. Our preliminary data suggest that the composition of the niche in certain B-ALL patients is governed by osteochondral cells, though further investigation is needed to shed light into this process.

The aim of this project is to unravel the communication network of ALL cells and skeletal progenitor cells in the bone marrow microenvironment.

To understand the cell-cell communication dynamics we will use single cell RNA sequencing of leukemic cells and FACs-sorted skeletal progenitor cells from diagnostic bone marrow samples. Cellular communication pathways will then be probed in our co-cultures of patient-derived ALL cells grown in direct contact with human iPSC-derived MSC (iMSC) (Cell Rep Med. 2022 Aug 16;3(8):100717.). CRISPR-Cas technology will be implemented to validate the findings on the communication circuitry. To further decipher the interplay of leukemic blasts and the osteochondral niche, we will develop a 3D co-culture system using miniature bone/cartilage particles. Spatial transcriptomics and confocal microscopy will be applied to investigate in a unique setting the mechanisms that govern leukemogenesis in the osteochondral niche.