Nardilysin determines hematopoietic stem cell fitness by regulating protein synthesis.

Nardilysin (NRDC) is a multifunctional protein required for maintaining homeostasis in various cellular and tissue contexts. However, its role in hematopoietic stem cells (HSCs) remains unclear. Here, through the conditional deletion of NRDC in hematopoietic cells, we demonstrate that NRDC is required for HSCs expansion in vitro and the reconstitution of hematopoiesis in vivo after transplantation. We found NRDC-deficient HSCs lose their self-renewal ability and display a preferential bias to myeloid differentiation in response to replication stress. Transcriptome data analysis revealed the upregulation of heat shock response-related genes in NRDC-deficient HSCs. Additionally, we observed increased protein synthesis in cultured NRDC-deficient HSCs. Thus, loss of NRDC may cause the inability to control protein synthesis in response to replication induced protein stress, leading to the impaired HSC self-renewal ability. This highlights a novel model of action of NRDC specifically in HSCs.

Prognostic impact of complex and/or monosomal karyotypes in post-transplant poor cytogenetic acute myeloid leukaemia: A quantitative approach.

To evaluate the prognostic impact of complex karyotype (CK) and/or monosomal karyotype (MK) in combination with various clinical factors on allogeneic stem cell transplantation (HSCT) outcomes of patients with acute myeloid leukaemia (AML), we analysed the registry database of adult AML patients who underwent allogeneic HSCT between 2000 and 2019 in Japan. Among 16 094 patients, those with poor cytogenetic risk (N = 3345) showed poor overall survival (OS) after HSCT (25.3% at 5 years). Multivariate analyses revealed that CK and/or MK (hazard ratio [HR], 1.31 for CK without MK; 1.27 for MK without CK; and 1.73 for both), age at HSCT ≥50 years (HR, 1.58), male sex (HR, 1.40), performance status ≥2 (HR, 1.89), HCT-CI score ≥3 (HR, 1.23), non-remission status at HSCT (HR, 2.49), and time from diagnosis to HSCT ≥3 months (HR, 1.24) independently reduced post-HSCT OS among patients with poor cytogenetic risk AML. A risk scoring system based on the multivariate analysis successfully stratified patients into five distinct groups for OS. This study confirms the negative effects of CK and MK on post-HSCT outcomes, and offers a powerful risk scoring system for predicting prognoses after HSCT among AML patients with unfavourable cytogenetics.

Development of a quantitative prediction model for peripheral blood stem cell collection yield in the plerixafor era.

BACKGROUND AIMS: Predicting autologous peripheral blood stem cell (PBSC) collection yield before leukapheresis is important for optimizing PBSC mobilization and autologous stem cell transplantation (ASCT) for treating hematological malignancies. Although guidelines for plerixafor usage based on peripheral blood CD34+ (PB-CD34+) cell count are available, their predictive performance in the real world remains unclear. METHODS: This study retrospectively analyzed 55 mobilization procedures for patients with non-Hodgkin lymphoma or multiple myeloma and developed a novel quantitative prediction model for CD34+ cell collection yield that incorporated four clinical parameters available the day before leukapheresis; namely, PB-CD34+ cell count the day before apheresis (day -1 PB-CD34+), number of prior chemotherapy regimens, disease status at apheresis and mobilization protocol. RESULTS: The effects of PB-CD34+ cell counts on CD34+ cell collection yield varied widely per patient characteristics, and plerixafor usage was recommended in patients with poorly controlled disease or those with a history of heavy pre-treatments even with abundant day -1 PB-CD34+ cell count. This model suggested a more proactive use of plerixafor than that recommended by the guidelines for patients with poor pre-collection condition or those with a higher target number of CD34+ cells. Further, the authors analyzed the clinical outcomes of ASCT and found that plerixafor use for stem cell mobilization did not affect short- or long-term outcomes after ASCT. CONCLUSIONS: Although external validations are necessary, the results can be beneficial for establishing more effective and safer mobilization strategies.

The Relationship Between Mean Platelet Volume and Fasting Plasma Glucose and HbA1c Levels in a Large Cohort of Unselected Health Check-Up Participants.

BACKGROUND: Larger platelets are more active and mean platelet volume (MPV) is an indicator of platelet activation and an independent risk factor of cardiovascular diseases. While MPV is reported to be higher in diabetic patients, the relationship between MPV and glycemic parameters in general population remains inconclusive. METHODS: In this cross-sectional study, we studied relationship between MPV and fasting plasma glucose (FPG) and HbA1c levels in 38,204 unselected participants of general health check-up aged 20 years or older in the year of 2014 who were considered to be representative of the general population. Individuals with known diabetes, coronary artery disease and/or cerebrovascular disease who were on drug therapy and those with platelet counts below 100 × 109/L or above 400 × 109/L were excluded. RESULTS: The mean age of the individuals was 52.3 ± 12.1 years and 46.1% were male. There were positive associations between MPV and both FPG (r = 0.066; P < 0.001) and HbA1c (r = 0.025; P < 0.001) levels when all individuals were analyzed as a whole. While the association was only marginal in individuals with HbA1c levels below 6.5% (r = 0.009; P = 0.068), it was significant in those with HbA1c ≥ 6.5% (r = 0.138; P < 0.001). When the individuals were categorized into four groups according to the HbA1c values: HbA1c < 5.5%, 5.5% ≤ HbA1c < 6.0%, 6.0% ≤ HbA1c < 6.5%, and HbA1c ≥ 6.5%, the mean MPV was virtually same among groups with HbA1c level < 6.5% and that of the individuals with HbA1c ≥ 6.5 was significantly higher than groups with lower HbA1c levels. Multivariate analyses adjusted with age and sex showed the same results. CONCLUSION: FPG and HbA1c appeared to be associated with MPV in unselected health check-up participants; however, the association between glycemic state and MPV was apparent only in individuals with impaired glycemic control and only marginal in those with normal glycemic control. The clinical significance of the associations warrants further study.