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The Proteogenomic Subtypes of Acute Myeloid Leukemia

ABSTRACT: Acute myeloid leukemia (AML) is an aggressive blood cancer with poor prognosis. We report a comprehensive proteogenomic analysis of bone-marrow biopsies from 252 uniformly treated AML patients to elucidate the molecular pathophysiology of AML in order to inform future diagnostic and therapeutic approaches. In addition to in-depth quantitative proteomics, our analysis includes cytogenetic profiling and DNA/RNA sequencing. We identify five proteomic AML subtypes, each reflecting specific biological features spanning genomic boundaries. Two of these proteomic subtypes correlate with patient outcome, but none are exclusively associated with specific genomic aberrations. Remarkably, one subtype (Mito-AML), which is only captured in the proteome, is characterized by high expression of mitochondrial proteins and confers poor outcome, with reduced remission rate and shorter overall survival upon treatment with intensive induction chemotherapy. Functional analyses reveal that Mito-AML is metabolically wired towards stronger complex I dependent respiration and is more responsive to treatment with the BCL2 inhibitor venetoclax.

PROVIDER: EGAS00001005950 | EGA |

REPOSITORIES: EGA

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The Proteogenomic Subtypes of Acute Myeloid Leukemia

Project description:Acute myeloid leukemia (AML) is an aggressive blood cancer with poor prognosis. We performed a comprehensive proteogenomic analysis of bone-marrow biopsies from 252 uniformly treated AML patients to elucidate the molecular pathophysiology of AML in order to inform future diagnostic and therapeutic approaches. In addition to in-depth quantitative proteomics, our analysis included cytogenetic and mutation profiling, and RNA sequencing. This identified five proteomic AML subtypes, each reflecting specific biological features spanning genomic boundaries. Two of these subtypes were correlated with patient outcome, but none exclusively associated with specific genomic aberrations. Remarkably, one subtype (Mito-AML), which was only captured in the proteome, was characterized by high expression of mitochondrial proteins and showed poor outcome, with reduced remission rate and shorter overall survival upon treatment with intensive induction chemotherapy. Functional analyses revealed that Mito-AML is metabolically wired towards stronger complex Idependent respiration and is more responsive to treatment with the BCL2-inhibitor venetoclax.

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