Hematology:

CONCLUSIONS: These data reveal a novel regulation of lysine β-hydroxybutyrylation on PHD2 and demonstrate a promising and therapeutic role for β-OHB/PHD2 in effectively accelerating neovascularization and preserving heart function after cardiac ischemia.

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Over the course of the last decade, genomic studies in the context of normal human hematopoiesis have provided new insights into the early pathogenesis of myeloproliferative neoplasms (MPN). A preclinical phase of MPN, termed clonal hematopoiesis was identified and subsequent lineage tracing studies revealed a multi-decade long time interval from acquisition of an MPN phenotypic driver mutation in a hematopoietic stem cell to the development of overt MPN. Multiple germline variants associated with MPN risk have been identified through genome-wide association studies and in some cases functional interrogation of the impact of the variant has uncovered new insights into hematopoietic stem cell biology and MPN development. Increasingly sophisticated methods to study clonal contributions to human hematopoiesis and measure hematopoietic stem cell fitness have helped to discern the biology underlying the tremendous clinical heterogeneity observed in MPN. Despite these advances, significant knowledge gaps remain, particularly with respect to germline genetic contributors to both MPN pathogenesis and phenotypic diversity, as well as limitations in the ability to prospectively quantify rates of clonal expansion in individual MPN patients. Ultimately, we envisage a personalized approach to MPN care in the future, in which an individualized genetic assessment can predict MPN trajectory and this information will be used to inform and guide therapy. MPN is particularly amenable to precision medicine strategies and our increased understanding of the evolution of MPN from normal blood stem cells provides a unique opportunity for early therapeutic intervention approaches and potentially MPN prevention strategies.

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We discuss the mechanisms of AML immune evasion including loss or downregulation of MHC class I and II, reduced TRAIL receptor expression, inhibitory metabolite production, inhibitory ligand expression, impaired proinflammatory cytokine production, and AML niche alterations.

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Philadelphia-chromosome negative myeloproliferative neoplasms (MPN) are hematopoietic stem disorders with a risk of progression to an accelerated phase (AP) or blast phase (BP) that is influenced by clinical, pathological, cytogenetic, and molecular variables. Overall survival of patients with MPN-AP/BP is limited with current treatment approaches, particularly in those patients who cannot receive an allogeneic hematopoietic stem cell transplant (allo-HCT). In addition, long-term survival with allo-HCT is predominantly seen in chronic-phase MPN, which suggests that the ideal time for intervention may be before the MPN evolves to AP/BP. In this review we focus on the risk factors for progression to MPN-AP/BP, identification of high-risk chronic-phase MPN, potential early-intervention strategies, and considerations around the timing of allo-HCT. We also summarize current survival outcomes of patients with MPN-AP/BP, discuss the uncertainty around how to best gauge response to therapy, and outline clinical trial considerations for this population of patients. Lastly, we highlight future directions in the management of high-risk MPN.