Qian Ran

ANKRD26-related thrombocytopenia 2 (THC2) is a rare inherited platelet disorder caused by germ line variants in the 5′ untranslated region (UTR) of ANKRD26. Although prior studies using in vitro models or isolated case reports have suggested impaired megakaryopoiesis as a central mechanism, detailed insights have remained elusive, primarily due to the rarity, fragility, and heterogeneity of megakaryocytes (MKs). Here, we present a comprehensive, crossvalidated analysis of bone marrow samples from 4 independent patients with THC2, integrating single-cell transcriptomics and ex vivo functional profiling. Across all patients, we analyzed CD34+ hematopoietic stem and progenitor cells (HSPCs; 47 281 THC2 HSPCs vs 51 907 control cells) and primary MKs (pMKs; 7309 THC2 pMKs vs 5077 control cells), uncovering a consistent pattern of MK progenitors (MkP) expansion and a marked reduction in polyploid MKs, indicating a conserved pathophysiologic phenotype. In our index patient, we identified the 5′ UTR single-nucleotide variant in ANKRD26 that led to significantly elevated expression across 4 MK lineage subsets, spanning multipotent progenitors, common myeloid progenitors, MK-erythroid progenitors, and MkP as well as in terminally enriched pMKs. Confocal imaging localized ANKRD26 to the centrosome, implicating it in mitotic regulation during MK maturation. Mechanistically, we discovered that elevated ANKRD26 induces apoptosis in polyploid MKs via JUNB-mediated transcriptional activation of CDKN1A (p21), operating independently of the canonical p53-PIDDosome axis. This multipatient study provided the most comprehensive cellular and molecular portrait of ANKRD26-driven thrombocytopenia to date, offering novel insights into defective megakaryopoiesis and identifying candidate therapeutic targets to restore platelet production.

Induction of fetal hemoglobin (HbF) expression is a promising therapeutic approach for hemoglobinopathies. HbF is primarily regulated by hypoxia-inducible

Corrigendum: Multifunctions of CRIF1 in cancers and mitochondrial dysfunction

Sustaining proliferative signaling and enabling replicative immortality are two important hallmarks of cancer. The complex of cyclin-dependent kinase (CDK) and its cyclin plays a decisive role in the transformation of the cell cycle and is also critical in the initiation and progression of cancer. CRIF1, a multifunctional factor, plays a pivotal role in a series of cell biological progresses such as cell cycle, cell proliferation, and energy metabolism. CRIF1 is best known as a negative regulator of the cell cycle, on account of directly binding to Gadd45 family proteins or CDK2. In addition, CRIF1 acts as a regulator of several transcription factors such as Nur77 and STAT3 and partly determines the proliferation of cancer cells. Many studies showed that the expression of CRIF1 is significantly altered in cancers and potentially regarded as a tumor suppressor. This suggests that targeting CRIF1 would enhance the selectivity and sensitivity of cancer treatment. Moreover, CRIF1 might be an indispensable part of mitoribosome and is involved in the regulation of OXPHOS capacity. Further, CRIF1 is thought to be a novel target for the underlying mechanism of diseases with mitochondrial dysfunctions. In summary, this review would conclude the latest aspects of studies about CRIF1 in cancers and mitochondria-related diseases, shed new light on targeted therapy, and provide a more comprehensive holistic view.

Coronavirus disease 2019 (COVID-19) has become a global pandemic with a high rate of transmission. Currently, there is a lack of vaccines and specific drugs for this newly-emerged virus. Timely diagnosis and treatment, as well as isolation of patients and virus carriers, contribute to the effective prevention and control of this epidemic. This review focuses on early stage COVID-19 diagnosis methods and strategies, highlighting the guiding role of laboratory indicators on treatment strategy formulation, and prognosis assessments.

Background: Bone marrow stromal cells (BMSCs) are extensively used in regeneration therapy and cytology experiments simulate how BMSCs respond to radiation. Due to the small number and the heterogeneity of primary isolated BMSCs, extensive in vitro expansion is usually required before application, which affects the cellular characteristics and gene expression of BMSCs. However, whether the radiation response of BMSCs changes during in vitro expansion is unclear. Methods: In this study, BMSCs were passaged in vitro and irradiated at passage 6 (P6) and passage 10 (P10). Then, apoptosis, the cell cycle, senescence, the cytokine secretion and the gene expression profile were analysed for the P6, P10, and non-irradiated (control) BMSCs at different post-irradiation time points. Results: The P6 BMSCs had a lower percentage of apoptotic cells than the P10 BMSCs at 24 and 48 h post-irradiation but not compared to that of the controls at 2 and 8 h post-irradiation. The P6 BMSCs had a lower percentage of cells in S phase and a higher percentage in G1 phase than the P10 BMSCs at 2 and 8 h post-irradiation. The radiation had similar effects on the senescent cell level and impaired immunomodulation capacity of the P6 and P10 BMSCs. Regardless of whether they were irradiated, the P6 and P10 BMSCs always expressed a distinctive set of genes. The upregulated genes were enriched in pathways including the cell cycle, DNA replication and oocyte meiosis. Then, a subset of conserved irradiation response genes across the BMSCs was identified, comprising 12 differentially upregulated genes and 5 differentially downregulated genes. These genes were especially associated with the p53 signaling pathway, DNA damage and DNA repair. Furthermore, validation experiments revealed that the mRNA and protein levels of these conserved genes were different between the P6 and P10 BMSCs after irradiation. Weighted gene co-expression network analysis supported these findings and further revealed the effects of cell passage on the irradiation response in BMSCs. Conclusion: The results indicated that cell passage in vitro affected the irradiation response of BMSCs via molecular mechanisms that mediated differences in apoptosis, the cell cycle, senescence and the cytokine secretion. Thus, accurate cell passage information is not only important for transplantation therapy but also for future studies on the radiation response in BMSCs.

Irradiation can greatly inhibit osteogenesis of bone marrow mesenchymal stem cells (BM-MSCs). However, the mechanism remains unclear.