Pathways, Processes, and Candidate Drugs Associated with a Hoxa Cluster-Dependency Model of Leukemia

High expression of the cluster correlates with poor clinical outcome in acute myeloid leukemias, particularly those harboring rearrangements of the mixed-lineage-leukemia gene ( ). Whilst decreased expression acts as a readout for candidate experimental therapies, the necessity of the cluster for leukemia maintenance has not been fully explored. Primary leukemias were generated in hematopoietic stem/progenitor cells from responsive transgenic mice for conditional deletion of the locus. deletion resulted in reduced proliferation and colony formation in which surviving leukemic cells retained at least one copy of the cluster, indicating dependency. Comparative transcriptome analysis of wild type and deleted leukemic cells identified a unique gene signature associated with key pathways including transcriptional mis-regulation in cancer, the Fanconi anemia pathway and cell cycle progression. Further bioinformatics analysis of the gene signature identified a number of candidate FDA-approved drugs for potential repurposing in high expressing cancers including MLLr leukemias. Together these findings support dependency for an leukemia on expression and identified candidate drugs for further therapeutic evaluation.