Details

Autor(en) / Beteiligte

• Palau, Anna
• Segerberg, Filip
• Lidschreiber, Michael
• Lidschreiber, Katja
• Naughton, Aonghus J
• Needhamsen, Maria
• Jung, Lisa Anna
• Jagodic, Maja
• Cramer, Patrick
• Lehmann, Sören
• Carlsten, Mattias
• Lennartsson, Andreas

Titel

Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells

Ist Teil von

• Leukemia, 2023-09, Vol.37 (9), p.1830-1841

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2023

Link zum Volltext

Quelle

Nexis

Beschreibungen/Notizen

• 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.