GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE268nnn/GSE268003/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE268003GEOGSEfalseAML-PDXs Accelerate Development of Novel Drug Combinations for KMT2A-rearranged Acute Myeloid leukemiaIn 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.2026/04/09GSE268003GSM8283769GSM8283766GSM8283765GSM8283768GSM8283767GSM8283773GSM8283772GSM8283775GSM8283753GSM8283774GSM8283771GSM8283770GSM8283759GSM8283758GSM8283777GSM8283755GSM8283754GSM8283776GSM8283757GSM8283779GSM8283778GSM8283756GSM8283762GSM8283783GSM8283761GSM8283764GSM8283763GSM8283780GSM8283760GSM8283782GSM828378124676268003Homo sapiens[41576348]