AML-343: Loss of H3K27 Methylation Identifies Poor Outcomes in Adult-Onset Acute Lymphoblastic and Myeloid Leukemia

Abstract

ContextAcute leukemia is an (epi)genetically heterogeneous disease. The intensity of treatment is currently guided by cytogenetic and molecular genetic risk classifications; however, these incompletely predict outcomes, requiring additional information for more accurate predictions.ObjectiveWe aimed to identify potential prognostic implications of epigenetic modification of histone proteins in relation to driver mutations in chromatin, splicing and transcriptional regulators in adult-onset acute lymphoblastic (ALL) and myeloid leukemia (AML).DesignBone marrow (BM) and peripheral blood (PB) samples were collected from 114 newly diagnosed B-cell ALL, 14 T-cell ALL, and 241 AML patients who were admitted at the MD Anderson Cancer Center (MDACC) between September 1991 and March 2007. Proteomic profiling was performed using reverse phase protein array and additional mutational analysis was performed on 65 AML BM aspirates.SettingH3K4Me2, H3K4Me3 and H3K27Me3 levels were evaluated along with the expression of 227 other protein antibodies at time of diagnosis.Patients or other participantsPatient's ages ranged from 16 to 81 years (median=40±16) in ALL and from 17 to 87 years (median=64±16) in AML.InterventionsPatients were treated according to standard MDACC treatment protocols.Main outcome measuresOverall survival was considered as the primary study outcome.ResultsH3K4Me2, H3K4Me3 and H3K27Me3 were significantly higher in AML than in ALL. In AML, greater loss of H3K27Me3 was associated with increased proliferative potential and shorter overall survival in the whole patient population (HR=0.64, 95%CI=0.47-0.87, p=0.004) and in subsets, e.g. cytogenetically normal AML (HR=0.62, 95%CI=0.40-0.97, p=0.03) and IDH1 mutated patients (HR=0.21, 95%CI=0.062-0.72, p=0.009). H3K27Me3 was lower in ASXL1, BCOR, U2AF1 and SRSF2 mutated subgroups (p<0.05). Moreover, AML patients with decreased H3K27Me3 demonstrated an upregulated anti-apoptotic phenotype. In ALL, levels of histone methylation correlated with response to tyrosine kinase inhibitor in patients who carried the Philadelphia cytogenetic aberration and prior smoking behavior.ConclusionsProteomic profiling of histone modifications has clinical implications in acute leukemia and support the idea that epigenetic patterns contribute to a more accurate picture of the leukemic state and complement cytogenetic and molecular genetic subgrouping. H3K27Me3 measurement might be a suitable method to improve acute leukemia outcome prediction and subsequent treatment intensity stratification in selected subgroups.