IDH 突变 AML 中表观遗传转录调控紊乱导致对 NK 细胞的敏感性增加

Isocitrate dehydrogenase (IDH) mutations are found in 20% of acute myeloid leukemia (AML) patients.

However, only 30-40% of the patients respond to IDH inhibitors (IDHi).

We aimed to identify a molecular vulnerability to tailor novel therapies for AML patients with IDH mutations.

We characterized the transcriptional and epigenetic landscape with the IDH2i AG-221, using an IDH2 mutated AML cell line model and AML patient cohorts, and discovered a perturbed transcriptional regulatory network involving myeloid transcription factors that were partly restored after AG-221 treatment.

In addition, hypermethylation of the HLA cluster caused a down-regulation of HLA class I genes, triggering an enhanced natural killer (NK) cell activation and an increased susceptibility to NK cell-mediated responses.

Finally, analyses of DNA methylation data from IDHi-treated patients showed that non-responders still harbored hypermethylation in HLA class I genes.

In conclusion, this study provides new insights suggesting that IDH mutated AML is particularly sensitive to NK cell-based personalized immunotherapy.