![]() Notably, the dysregulation of histone post-translational modifications (PTMs) has been associated with several cancers including colorectal cancer (CRC). This approach has the potential to accelerate the unbiased target identification for immunotherapy of AML.Īlteration of epigenetic modifications plays an important role in human cancer. ![]() CONCLUSION: Taken together, we demonstrate the feasibility of a highly optimized surfaceome detection method to interrogate the entire AML surfaceome directly from primary patient samples and integrate this data with gene expression and mutational burden data to achieve a robust, multiomic target identification platform. Integrin beta-7 showed the most promising combination of expression in patient AML samples, and low or absent expression on healthy hematopoietic tissue. Seventy-six proteins were selected as potential candidates for further investigation of which we validated the most promising novel candidate markers, and identified CD148, ITGA4 and Integrin beta-7 as promising targets in AML. We integrated this data with gene expression and mutational burden data to curate a set of robust putative target antigens. Using primary AML patient samples, we were able to identify a total of 621 surface proteins comprising the AML surfaceome. RESULTS: Our protocol modifications allowed us to double the yield in identified proteins and increased the specificity from 54 to 80.4% compared to previous approaches. Finally, we validated our findings in a separate cohort of AML patient samples. We then further curated this AML surfaceome to exclude antigens expressed on healthy tissues and integrated mutational burden data from hematologic cancers to further enrich for targets which are likely to be essential to leukemia biology. METHODS: Here, we optimized the Cell Surface Capture protocol to enable direct interrogation of primary patient samples and applied our optimized protocol to a set of samples from patients with acute myeloid leukemia (AML) to generate the AML surfaceome. Yet, direct utilization of primary patient samples has been limited by the considerable number of viable cells needed. The Cell Surface Capture technology provides an unbiased, discovery-driven approach to map the surface proteins on cells of interest. To this end, unbiased approaches for surface protein detection are limited and integration with other data types, such as gene expression and somatic mutational burden, are poorly utilized. Collectively, our findings provide a framework for understanding how cells orchestrate histone supply and employ targeted deposition of modified histones to underpin specialized chromatin states.īACKGROUND: Immunotherapy of acute myeloid leukemia has experienced considerable advances, however novel target antigens continue to be sought after. Hereby, DAXX provides a molecular mechanism for de novo H3K9me3 deposition and heterochromatin assembly. We show that DAXX provides a unique functionality to the histone chaperone network, recruiting histone methyltransferases to promote H3K9me3 catalysis on new histone H3.3-H4 prior to deposition onto DNA. We identify previously uncharacterized histone-dependent complexes and predict the structure of the ASF1 and SPT2 co-chaperone complex, expanding the role of ASF1 in histone dynamics. Using exploratory interactomics, we define the interplay between human histone H3-H4 chaperones in the histone chaperone network. ![]() They cooperate through the formation of histone co-chaperone complexes, but the crosstalk between nucleosome assembly pathways remains enigmatic. Collectively, this argues that epigenetic inheritance of histone modifications maintains a correctly balanced and dynamic chromatin landscape able to support mammalian cell differentiation.Ī multitude of histone chaperones are required to support histones from their biosynthesis until DNA deposition. Furthermore, developmental competence was diminished, correlating with impaired exit from pluripotency. ![]() MCM2-2A mutation challenged dynamic transitions in cellular states across the cell cycle, enhancing naïve pluripotency and reducing lineage priming in G1. Moreover, H3K9me3 loss at repeats caused derepression and H3K27me3 redistribution across bivalent promoters correlated with misexpression of developmental genes. This included widespread spurious deposition of repressive modifications, suggesting elevated epigenetic noise. Asymmetric segregation of parental histones H3-H4 in MCM2-2A mutants compromised mitotic inheritance of histone modifications and globally altered the epigenome. Here we show that transmission of histone-based information during DNA replication maintains epigenome fidelity and embryonic stem cell plasticity. How this may sustain the epigenome and cell identity remains unknown. Modified parental histones are segregated symmetrically to daughter DNA strands during replication and can be inherited through mitosis.
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