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

Area of Science:

• * Molecular biology
• * Cancer research
• * Hematology

Background:

• * High expression of the HOXA cluster is associated with poor clinical outcomes in acute myeloid leukemias (AML), especially those with mixed-lineage-leukemia gene rearrangements (MLLr).
• * The necessity of the HOXA cluster for leukemia maintenance remains underexplored, despite decreased HOXA expression being a marker for experimental therapies.

Purpose of the Study:

• * To investigate the essential role of the HOXA cluster in maintaining MLLr AML.
• * To identify potential therapeutic strategies by analyzing the gene expression changes following HOXA cluster deletion.

Main Methods:

• * Conditional deletion of the Hoxa locus in hematopoietic stem/progenitor cells from Cre-responsive transgenic mice to generate primary leukemias.
• * Comparative transcriptome analysis of Hoxa wild-type and deleted leukemic cells.
• * Bioinformatics analysis of identified gene signatures.

Main Results:

• * Hoxa deletion led to reduced proliferation and colony formation in leukemic cells.
• * Surviving leukemic cells retained at least one copy of the Hoxa cluster, indicating dependency.
• * Transcriptome analysis revealed a unique gene signature linked to transcriptional misregulation, Fanconi anemia pathway, and cell cycle progression.

Conclusions:

• * MLLr leukemia is dependent on HOXA cluster expression for maintenance.
• * A gene signature associated with HOXA deletion can identify candidate FDA-approved drugs for repurposing in HOXA-high cancers, including MLLr leukemias.