AML-PDXs Accelerate Development of Novel Drug Combinations for KMT2A-rearranged Acute Myeloid leukemia

In pediatric acute myeloid leukemia (AML) the achievement of complete remission with standard treatments is obtained in most cases, but relapse still occurs in 30% of patients with greater incidence found in those patients showing high-risk AML genetic features. There is, therefore, an urgent need to identify novel effective therapies for children with relapsed-refractory leukemia. We established 26 AML patient-derived xenografts (PDXs), through sequential engraftment in NSG mice, including 14 high-risk genetic subtypes. Results confirmed AML-PDXs robustly resemble the original AML in terms of immunophenotype, genomic, and transcriptomic profiles, offering a comprehensive view of the disease complexity, useful to tailor therapies. In particular, by whole-exome sequencing, we evidenced a high intra-tumoral heterogeneity and we identified variants of each founder clone being perpetuated from patient-AML blasts to PDX. Then, we explored the efficacy of several drugs predicted to target these genomic variants in a three-dimensional in vitro culture and demonstrated that targeting variants of theWnt/β-cateninpathway is a promising strategy to reduce AML subclone fitness. By RNA-sequencing we observed thatKMT2A-rearranged AML and AML-PDXs shared aberrantly activated metabolic and stem expression signatures and documented that both IACS-010759 and Asparaginase, tailored to target transcriptome aberrancies, if combined with Venetoclax, mediated a significantly prolonged PDXs survival compared to Venetoclax used as single agent. Overall, our data indicate that AML-PDX models are unique tools for capturing AML heterogeneity, offering the possibility to target cancer cells in their multiple aspects, this increasing the chance to fully eradicate leukemia cells.