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

Abstract

High expression of the HOXA cluster correlates with poor clinical outcome in acute myeloid leukemias, particularly those harboring rearrangements of the mixed-lineage-leukemia gene (MLLr). Whilst decreased HOXA expression acts as a readout for candidate experimental therapies, the necessity of the HOXA cluster for leukemia maintenance has not been fully explored. Primary leukemias were generated in hematopoietic stem/progenitor cells from Cre responsive transgenic mice for conditional deletion of the Hoxa locus. Hoxa deletion resulted in reduced proliferation and colony formation in which surviving leukemic cells retained at least one copy of the Hoxa cluster, indicating dependency. Comparative transcriptome analysis of Hoxa 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 HOXA expressing cancers including MLLr leukemias. Together these findings support dependency for an MLLr leukemia on Hoxa expression and identified candidate drugs for further therapeutic evaluation.

Identification of Early Recurrence Factors in Childhood and Adolescent B-Cell Acute Lymphoblastic Leukemia Based on Integrated Bioinformatics Analysis

“…The HOXA7 gene is a member of the homeobox (HOX) gene family, which plays vital roles in hematopoiesis and cell differentiation ( 25 ). Previous research has shown that the gene HOXA7 is overexpressed in MLL-fusion leukemias, which commonly have very poor outcomes ( 26 – 29 ). The proteins encoded by S100A10 and S100A11 are members of the S100 family.…”

Hydrogel-Based Pre-Clinical Evaluation of Repurposed FDA-Approved Drugs for AML

“…We and others have demonstrated the efficacy of several drugs targeted towards other diseases (e.g., sodium valproate) in the clinical setting against subtypes of AML [ 9 , 13 ]. More recently, using a combination of connectivity mapping in a conditional model of Mixed-Lineage Leukemia (MLL) AML and drug similarity analysis, we identified FDA-approved candidate drugs (including Salinomycin, Atorvastatin, and Vidofludimus) that potentially target HOXA -dependency in MLL-AF9 leukemia [ 14 ]. For candidate drug studies, the human THP-1 cell line and murine mAF9 primary cells were selected as matched exemplars of AML models that harbor the MLL-AF9 translocation.…”