Circulating Histone Profiling in Acute Myeloid Leu-kaemia: Longitudinal Dynamics and Cross-Sectional Comparison with Myelodysplastic Neoplasms with Increased Blasts

Circulating histones are increasingly recognised as biologically relevant components of extracellular chromatin, but their composition and treatment-associated dynamics in acute myeloid leukaemia (AML) remain poorly defined. In this prospective single-centre observational study, we profiled 13 histone measures by ImageStream imaging flow cy-tometry in 31 plasma samples from 15 newly diagnosed AML patients at diagnosis/day 7/day 28 (n=15/10/6), with 30 healthy controls and 12 patients with myelodysplastic neoplasms with increased blasts. At diagnosis, nine of 13 measures differed from controls after false discovery rate (FDR) correction, defining a bidirectional profile with higher H2A-, H2B- and macroH2A1-associated measures and lower H3, H4 and H3/H4; the largest differences included in-creased macroH2A1.1 (7.07% vs. 0.47%; δ=0.98) and reduced H4 (0.14% vs. 3.25%; δ=−0.87). By day 7, five measures remained FDR-significant, all decreasing: H4, H3/H4 and the three tetrameric complexes. At day 28, no paired comparison remained FDR-significant; however, H3/H4 showed a significant overall temporal change across the six complete serial trajectories (q = 0.0334). Exploratory day-28 trajectories showed concordant decreases in all three tetrameric complexes in complete remission, with opposite changes in residual disease. MDS with increased blasts showed higher macroH2A1-containing tetrameric complexes than controls and AML. These findings support disease- and treatment-associated redistribution of circulating histone populations across myeloid neoplasia.