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

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.