The proteogenomic subtypes of acute myeloid leukemia

Although genetics have identified mutations and cytogenetic aberrations as driver events and drug targets in AML, there remains a mismatch between cytogenetic risk and patient outcomes. Hence, there is a strong medical need to elucidate the mechanisms governing the maintenance of AML and future efforts are needed to refine AML classification beyond genomic features, to improve biomarker identification and therapy stratification.

We report a comprehensive proteogenomic analysis of bone marrow biopsies from 252 adult AML patients. In addition to proteomics, our analysis includes cytogenetic profiling and DNA/RNA sequencing. We identify five proteomic AML subtypes, each reflecting specific biological features. Two of these subtypes correlate with patient outcome, but none are exclusively associated with specific genomic aberrations. One subtype (Mito-AML) is characterized by high expression of mitochondrial proteins and confers poor outcome, with shorter overall survival upon induction therapy. Analyses reveal that Mito-AML is metabolically biased towards stronger complex I dependent respiration and is more responsive to treatment with the BCL2 inhibitor venetoclax.

Publication History

Article published online:
17 May 2022