Remodelling of the bone marrow vasculature induced by venetoclax and azacitidine damage
The Bcl2 inhibitor venetoclax in combination with the hypomethylating agents azacitidine (ven/aza) has become increasingly utilised clinically for the treatment of haematological malignancies. Whilst its impact on the malignant cells have been extensively studied, its impact to the surrounding bone marrow microenvironment (BME) remains unexplored.  In this study, we report that ven/aza therapy causes significant damage to the BME of immunodeficient mice. Comparatively, high Bcl2 expression in the sinusoidal endothelial cell compartment (SEC) results in high sensitivity to ven/aza treatment, causing a loss of SECs and breakdown in cell-cell communication pathways in the endothelial cell (EC) network. Furthermore, our detailed transcriptomic and imaging studies reveal significant downregulation of essential adhesion molecules in residual SECs, leading to significant defects in human hematopoietic stem/progenitor cell (HSPC) homing and engraftment of hematopoietic stem cells (HSCs). Interestingly, although the vascular niche undergoes partial restoration from therapy induced damage, short-term exposure to ven/aza was sufficient to cause longer-term transcriptional changes to the EC compartment, negatively impacting HSC engraftment in mice receiving HSPC transplantation following endothelial cell recovery.  To conclude, our study showcases that maintaining SEC integrity in response to ven/aza therapy may play a key factor in achieving effective engraftment of donor derived HSCs. Overall design: Single cell RNA sequencing of murine bone marrow stroma from 3 conditions (Vehicle, Ven/aza, Recovery) hashed using Cell Multiplexing Oligos