Functional-genomic prioritization identifies MED12 as a candidate RNAi vulnerability in acute myeloid leukemia: evaluation of a T22 peptide-functionalized LNP-siRNA formulation.

BACKGROUND

Acute myeloid leukemia (AML) depends in part on transcriptional and epigenetic programs that can be difficult to target with conventional small molecules. RNA interference provides a potential approach to perturb such vulnerabilities, but target selection and intracellular siRNA delivery remain major challenges.

METHODS

Public dependency datasets and primary AML and normal hematopoietic expression resources were integrated to prioritize candidate RNAi vulnerabilities. A T22 peptide-functionalized lipid nanoparticle (TLNP) formulation carrying siMED12 was evaluated in OCI-AML3 cells, with RT-qPCR and CCK-8 validation in THP-1 cells. A systemic OCI-AML3 mouse model was used for exploratory assessment of survival and tolerability.

RESULTS

MED12 ranked highest in the integrated functional-genomic prioritization framework. In OCI-AML3 and THP-1 cells, TLNP-siMED12 produced replicated reductions in MED12 transcript abundance and cell viability across three independently initiated experiments. In OCI-AML3 cells, cellular uptake, free T22 competition, immunoblotting, apoptosis, migration and whole-well crystal violet-stained colony-like focus observations were each obtained once and are reported descriptively. In the systemic model, TLNP-siMED12 treatment was associated with prolonged survival; body weight, endpoint blood measurements and illustrative H&E images provided limited tolerability information.

CONCLUSION

Integrated functional-genomic prioritization identified MED12 as a candidate RNAi vulnerability in AML. TLNP-siMED12 produced reproducible transcript and viability responses in the evaluated AML models and was associated with prolonged survival in the systemic OCI-AML3 model. Hematopoietic selectivity, receptor-dependent delivery and in vivo target engagement remain to be established.