A common ground: an in silico assessment of the sources of intrinsic ex vivo resistance to venetoclax in acute myeloid leukemia

Venetoclax is a promising alternative for patients with acute myeloid leukemia who are considered unfit for conventional chemotherapy; however, its employment still faces challenges mostly related to drug resistance. Here, we provide further biological mechanisms underlying the previously described and potentially novel intrinsic sources of poor response to venetoclax departing from ex vivo response data. Acute myeloid leukemia data including FLT3 mutation status, gene expression data, and ex vivo response data were extracted from the publicly available BeatAML 1.0 study database and aided sample categorization that supported differential gene expression analysis that, in turn, supported gene set enrichment analysis. CIBERSORTx-based bulk RNA sequencing deconvolution of BeatAML 1.0 data allowed us to categorize samples according to their cell type content. We observed that inflammation-related gene sets, such as cytokines and inflammatory response, NLRP3 inflammasome activation, and activation of adaptive immune response, were concordantly positively enriched across all the conditions reported to be associated with poor ex vivo venetoclax response, whereas samples from good ex vivo responders' mostly enriched gene sets related to mitochondrial activity, and early myeloid progenitor cell molecular programs. Besides the alternative reliance on BCL2A1, we highlight inflammation as a common element present across multiple sources of venetoclax ex vivo response modulation in acute myeloid leukemia samples. Hence, a potential key modulator for venetoclax response.