Remodelling of the bone marrow vasculature induced by venetoclax and azacitidine damage
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Steven Ngo Giuseppe D'Agostino Despoina Papazoglou Fatihah Mohamad Nor Katja Finsterbusch Khadidja Habel Alessandra Ferrelli Fernando Dos Anjos Afonso Dominique Bonnet

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Abstract

The Bcl2 inhibitor venetoclax in combination with the hypomethylating agents azacitidine (ven/aza) has become increasingly utilized clinically for the treatment of many hematological malignancies. Whilst its effects on 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 mice. Comparatively high Bcl2 expression in the sinusoidal endothelial cell compartment (SEC) amongst all stromal subtypes, results in high sensitivity to ven/aza treatment, causing selective depletion of SECs and breakdown in cell-cell communication pathways in the endothelial cell (EC) network, leading to vascular leakiness in the BM. Furthermore, our detailed transcriptomic and imaging studies reveals 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) after ven/aza treatment. 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.