Abstract

While the molecular mechanisms of acute myeloid leukemia failure to venetoclax-based therapy have been recently clarified, the mechanisms whereby patients with myelodysplastic syndromes (MDS) acquire secondary resistance to venetoclax after an initial response remain to be elucidated. Here, we show for the first time that MDS hematopoietic stem cells (HSCs) can undergo hierarchical differentiation reprogramming toward a granulo-monocytic-biased transcriptional state through the acquisition or expansion of clones with an isolated trisomy 8 cytogenetic aberration and STAG2 or RUNX1 mutations. This hierarchical rewiring changes HSCs survival dependence from BCL-2-mediated anti-apoptotic pathways to TNF-induced pro-survival NF-{kappa}B signaling and overcomes venetoclax-mediated cytotoxic effect. These findings underscore the importance of close molecular monitoring of patients with MDS enrolled in clinical trials of venetoclax to prevent HSC transcriptional reprogramming before the disease becomes resistant to this therapy.