Direct functional HOXA9/DNA-binding competitors versus epigenetic inhibitors of HOXA9 expression on cell proliferation, death and differentiation processes in the model of MLL-rearranged acute myeloid leukemia.

Abstract

Recent progress in cancer treatment has led to the development of advanced therapies targeting specific oncogenic drivers, with, for instance, new small molecule-targeted agents, antibody-drug conjugates, peptide drugs, cell-based, or gene therapies. The key target may be either the mutated/fused protein itself or a protein whose expression is directly dysregulated and involved in proliferation, resistance to cell death, or other cellular processes associated with the oncogenic process. Identifying the best therapeutic strategy requires evaluating both inhibitors of the altered protein and the dysregulated oncogene linked to the pathology. Within this context, the MLL-rearranged subtype (MLL-r) of acute myeloid leukemia (AML) poses significant challenges due to unfavorable prognosis, frequent relapses, and treatment resistance. MLL-r AMLs are known to be addicted to the oncogene transcription factor HOXA9, with a differentiation blockade that relies on its ability to bind DNA. Recently, several MLL-r epigenetic complex inhibitors have been developed, some entering clinical trials. We identified and optimized two HOXA9 functional inhibitors, DB818 and DB1055, operating at the DNA-binding level. The present study compares the cellular effects of both indirect (epigenetic MLL inhibitors) and direct (DNA binding) HOXA9 inhibitors in two distinct pediatric MLL-r cell models, THP-1 and MV4-11. Our findings indicate that direct DNA-binding inhibition of HOXA9 by DB818 and DB1055 resulted in more favorable outcomes in facilitating leukemic cell differentiation, impairing uncontrolled proliferation, and promoting cell death. Thus, a direct DNA-binding inhibition of the addiction oncogene HOXA9 could represent an interesting opportunity for MLL-r therapy.