SUMMARY The ubiquitin-proteasome and autophagy-lysosome systems are major proteolytic pathways, whereas function of the Ub-independent proteasome pathway is yet to be clarified. Here, we investigated roles of the Ub-independent REGγ-proteasome proteolytic system in regulating metabolism. We demonstrate that mice deficient for the proteasome activator REGγ exhibit dramatic autophagy induction and are protected against high-fat diet (HFD)-induced liver steatosis through autophagy. Molecularly, prevention of steatosis in the absence of REGγ entails elevated SirT1, a deacetylase regulating autophagy and metabolism. REGγ physically binds to SirT1, promotes its Ub-independent degradation and inhibits its activity to deacetylate autophagy-related proteins, thereby inhibiting autophagy under normal conditions. Moreover, REGγ and SirT1 dissociate from each other through a phosphorylation-dependent mechanism under energy-deprived conditions, unleashing SirT1 to stimulate autophagy. These observations provide a function of the REGγ proteasome in autophagy and hepatosteatosis, underscoring mechanistically a cross-talk between the proteasome and autophagy degradation system in the regulation of lipid homeostasis.

U2AF1 mutations (U2AF1MT) occur commonly in myelodysplastic syndromes (MDS) without ring sideroblasts. The aim of this study was to investigate the clinical and biological implications of different U2AF1 mutation types in MDS. We performed targeted gene sequencing in a cohort of 511 MDS patients. Eighty-six patients (17%) were found to have U2AF1MT, which occurred more common in younger patients (P = .001) and represented ancestral lesions in a substantial proportion (71%) of cases. ASXL1MT and isolated +8 were significantly enriched in U2AF1MT-positive cases, whereas TP53MT, SF3B1MT, and complex karyotypes were inversely associated with U2AF1MT. U2AF subjects were enriched for isolated +8 and were inversely associated with complex karyotypes. U2AF1MT was significantly associated with anemia, thrombocytopenia, and poor survival in both lower-risk and higher-risk MDS. U2AF1 subjects had more frequently platelet levels of <50 × 10 /L (P = .043) and U2AF1 /U2AF1 subjects had more frequently hemoglobin concentrations at <80 g/L (P = .008) and more often overt fibrosis (P = .049). In conclusion, our study indicates that U2AF1MT is one of the earliest genetic events in MDS patients and that different types of U2AF1MT have distinct clinical and biological characteristics.

Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic disorders that are incurable with conventional therapy. Their incidence is increasing with global population aging. Although many genetic, epigenetic, splicing, and metabolic aberrations have been identified in patients with MDS, their clinical features are quite similar. Here, we show that hypoxia-independent activation of hypoxia-inducible factor 1α (HIF1A) signaling is both necessary and sufficient to induce dysplastic and cytopenic MDS phenotypes. The HIF1A transcriptional signature is generally activated in MDS patient bone marrow stem/progenitors. Major MDS-associated mutations (, and ) activate the HIF1A signature. Although inducible activation of HIF1A signaling in hematopoietic cells is sufficient to induce MDS phenotypes, both genetic and chemical inhibition of HIF1A signaling rescues MDS phenotypes in a mouse model of MDS. These findings reveal HIF1A as a central pathobiologic mediator of MDS and as an effective therapeutic target for a broad spectrum of patients with MDS. We showed that dysregulation of HIF1A signaling could generate the clinically relevant diversity of MDS phenotypes by functioning as a signaling funnel for MDS driver mutations. This could resolve the disconnection between genotypes and phenotypes and provide a new clue as to how a variety of driver mutations cause common MDS phenotypes. .

BackgroundChronic myelomonocytic leukemia (CMML) is a myeloid neoplasm classified in the myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) category. Molecular abnormalities are reported in about 90 % of patients with CMML. ASXL1 and SETBP1 mutations, but not TET2 or SFRS2 mutations are reported to be associated with prognosis.MethodsWe studied frequency of TET2, SRSF2, ASXL1 and SETBP1 mutations in 145 patients with CMML using Sanger sequencing, and determined the prognostic factors for OS. We also identified the predictive value of ASXL1 mutations (frameshift and nonsense mutations) through comparing the Mayo Prognostic Model with the Mayo Molecular Model.ResultsForty-seven (32 %) had a mutation in TET2, 42 (29 %), a mutation in SRSF2, 65 (45 %), a mutation (nonsense and frame-shift) in ASXL1 and 26 (18 %), a mutation in SETBP1. Significant variables in multivariable analysis of survival included ASXL1 (HR = 1.99 [1.20–3.28]; P = 0.007), hemoglobin <100 g/L (HR = 2.42 [1.40–4.19]; P = 0.002) and blood immature myeloid cells (IMCs) (HR = 2.08 [1.25–3.46]; P = 0.005). When our patients were analyzed using the Mayo Prognostic Model median OS were not reached, 26 months and 15 months (P = 0.014). An analysis using the Mayo Molecular Model identified 4 cohorts with median OS of not reached, 70 months, 26 months and 11 months (P < 0.001). Data fitting using our patients suggest the Molecular Mayo Model has significantly higher survival predictive power compared with Mayo Prognostic Model (P < 0.001, −2 log-likelihood ratios of 538.070 and 552.260).ConclusionsThere were high frequencies of mutations in TET2, SRSF2, ASXL1 and SETBP1 in patients with CMML. With the addition of ASXL1 frameshift and nonsense mutations, the Mayo Molecular Model fitted better than Mayo Prognostic Model of our patients.