Histone Modifications in Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. AML is a genetically heterogeneous disease relative to other tumor types; AMLs have a paucity of pathogenic mutations and chromosomal aberrations [29-35]. The Melnick research group and the proposed NRTDP form a unique collaborative opportunity to characterize both the epiproteome and the epigenome from patient samples in AML. Dr. Melnick’s group has established “Enhanced Reduced Representation Bisulfite Sequencing” to profile genome wide DNA methylation at base-pair resolution. This technique has been used to profile hundreds of AML patient samples. An unbiased and comprehensive study of histone modifications has not yet been performed in AML and the combination of the two techniques has the potential to establish novel epigenetic regulatory mechanisms in play in AML. The proposed NRTDP will continue to expand histone post-translational modification quantitation methods (TR&D 4). Preliminary testing has revealed a high level of reproducibility using fewer than one million cells. Applying TR&D 4 in combination with TR&D 1, we will work together with the Melnick group to drive toward ever-lower sample amounts and establish highly reproducible proteomic protocols for low input samples, an essential step in any study using human patient material. To address the hypothesis, we propose to perform epiproteomic profiling on clinical AML samples to determine the impact mutations in epigenetic modifiers have on histone modification patterns in this disease.