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Olaf Heidenreich/Josef Vormoor/Mauricio Ferrao Blanco

7B. RAS signalling in the leukemic niche

The stromal bone marrow niche is a highly specialized compartment, consisting of skeletal cells (mesenchymal stem cells, osteoblasts, chondrocytes and adipocytes) that regulate haematopoiesis and skeletal regeneration. In B-lineage acute lymphoblastic leukaemia, both microenvironment-mediated dependence and microenvironment-mediated resistance of the leukemic cells to anti-cancer therapy (chemotherapy, targeted therapy and immunotherapy) are key challenges. Leukemic cells actively reprogram their microenvironment to create a supportive niche, though the underlying mechanisms are poorly understood.

RAS signalling is a key pathway that mediates microenvironment-dependent resistance in ALL. In solid tumours, RAS signalling has been shown to be essential to reshape the microenvironment towards a more protective niche, stimulating adhesion, invasion and metastasis. However, not much is known about the effects of RAS signaling and the leukemic niche.

The aim of this project is to unravel how constitutively activated RAS signalling instructs the reciprocal communication network between acute lymphoblastic leukemia (ALL) and mesenchymal stem cells (MSC) and their progeny. Our ultimate goal is to identify exploitable vulnerabilities in this cell-cell interaction that give rise to more efficient and less toxic therapies for ALL.

In order to investigate the underlying mechanisms of RAS pathway driven communication of the leukemic cells with the microenvironment, we will make us of an ex vivo co-culture system, consisting  of patient-derived ALL cells grown in direct contact with primary human MSCs. Single cell multiome sequencing will be used to explore RAS-dependent communication between ALL and MSCs. We have also generated iPSC lines from human MSCs (iMSC) (Cell Rep Med. 2022 Aug 16;3(8):100717.) that will be genetically modified, e.g. CRISPR technology, to probe and validate connections relevant for RAS-dependent interactions. To further decipher the interplay of leukemic blasts and the stromal niche, we will develop a 3D co-culture system using miniature MSCs-derived bone/cartilage particles. Spatial transcriptomics and confocal microscopy will be applied to investigate in a unique setting the mechanisms that govern leukemogenesis in the niche.

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