Downregulation of autophagy is associated with poor clinical outcome after immunochemotherapy in patients with diffuse large B-cell lymphoma.

This study aimed to determine the expression levels of the autophagy markers Beclin-1 and p62 in patients with diffuse large B-cell lymphoma (DLBCL) and explore the association between autophagy and disease prognosis. The expression of Beclin-1 and p62 was investigated in patients with DLBCL and patients with reactive lymphoproliferative disease (RLD) using immunohistochemistry. The association between the clinical characteristics of patients with DLBCL and autophagy status was further analyzed. Beclin-1 levels were increased in RLD patients compared with those with DLBCL, but the difference was not statistically significant (p > 0.05). p62 levels in DLBCL patients were significantly higher than those in RLD patients (p < 0.05). Beclin-1 expression was associated only with the Ann Arbor stage (p < 0.05), whereas p62 expression was associated with the Ann Arbor stage, IPI score, extranodal involvement, and Ki-67 index (p < 0.05). Beclin-1 and p62 levels were not associated with short-term treatment efficacy in DLBCL patients. Survival analysis showed that Beclin-1 expression had no significant effect on 2-year progression-free survival (PFS) or overall survival (OS) (p > 0.05). However, high p62 expression in DLBCL patients was associated with reduced 2-year PFS compared with that of patients with low p62 expression (p < 0.05); the 2-year OS was not affected (p > 0.05). Our results demonstrate that autophagic activity affects the prognosis of DLBCL patients; the lower the autophagic activity, the shorter the PFS. Targeted p62 knockout may be a novel therapeutic strategy for the treatment of DLBCL patients.

被引量：- 发表：1970

Involvement of CREB3L1 in erythropoiesis induced by JAK2 exon 12 mutation.

CREB3L1, a gene encoding the endoplasmic reticulum stress transducer, is specifically overexpressed in platelet RNA from patients with myeloproliferative neoplasms (MPNs). However, the pathophysiological roles of CREB3L1 overexpression remain unclear. In the present study, we aimed to study CREB3L1 messenger RNA (mRNA) expression in the red blood cells (RBCs) of patients with MPN and its role in erythrocytosis. Elevated expression of CREB3L1 was exclusively observed in the RBCs of patients with polycythemia vera (PV) harboring JAK2 exon 12 mutations, but not in those harboring JAK2 V617F mutation or control subjects. In erythropoiesis, CREB3L1 expression was sharply induced in erythroblasts of bone marrow cells collected from patients with JAK2 exon 12 mutation. This was also evident when erythropoiesis was induced in vitro using hematopoietic stem and progenitor cells (HSPCs) with JAK2 exon 12 mutation. Interestingly, overexpression of CREB3L1 in RBCs was observed in patients with reactive erythrocytosis whose serum erythropoietin (EPO) levels exceeded 100 mIU/mL. Elevated CREB3L1 expression was also observed in the erythroblasts of a patient with acute erythroid leukemia. EPO-dependent induction of CREB3L1 was evident in erythroblasts differentiated from HSPCs in vitro, regardless of driver mutation status or MPN pathogenesis. These data strongly suggest that CREB3L1 overexpression in RBCs is associated with hyperactivation of the EPO receptor and its downstream molecule, JAK2. Short hairpin RNA (shRNA) knockdown of CREB3L1 expression in HSPCs blocked erythroblast formation in vitro. These results suggest that CREB3L1 is required for erythropoiesis in the presence of JAK2 exon 12 mutation or high level of EPO, possibly by antagonizing cellular stress.

被引量：- 发表：1970

A-to-I RNA editing and hematopoiesis.

Adenosine-to-inosine (A-to-I) RNA editing plays essential roles in modulating normal development and homeostasis. This process is catalyzed by adenosine deaminase acting on RNA (ADAR) family proteins. The most well-understood biological processes modulated by A-to-I editing are innate immunity and neurological development, attributed to ADAR1 and ADAR2, respectively. A-to-I editing by ADAR1 is also critical in regulating hematopoiesis. This review will focus on the role of A-to-I RNA editing and ADAR enzymes, particularly ADAR1, during normal hematopoiesis in humans and mice. Furthermore, we will discuss Adar1 mouse models that have been developed to understand the contribution of ADAR1 to hematopoiesis and its role in innate immune pathways.

被引量：- 发表：1970

Biomarkers for aging of blood - how transferable are they between mice and humans?

Aging significantly impacts the hematopoietic system, reducing its regenerative capacity and ability to restore homeostasis after stress. Mouse models have been invaluable in studying this process due to their shorter lifespan and the ability to explore genetic, treatment, and environmental influences on aging. However, not all aspects of aging are mirrored between species. This review compares three key aging biomarkers in the hematopoietic systems of mice and humans: myeloid bias, telomere attrition, and epigenetic clocks. Myeloid bias, marked by an increased fraction of myeloid cells and decreased lymphoid cells, is a significant aging marker in mice but is scarcely observed in humans after childhood. Conversely, telomere length is a robust aging biomarker in humans, whereas mice exhibit significantly different telomere dynamics, making telomere length less reliable in the murine system. Epigenetic clocks, based on DNA methylation changes at specific genomic regions, provide precise estimates of chronologic age in both mice and humans. Notably, age-associated regions in mice and humans occur at homologous genomic locations. Epigenetic clocks, depending on the epigenetic signatures used, also capture aspects of biological aging, offering powerful tools to assess genetic and environmental impacts on aging. Taken together, not all blood aging biomarkers are transferable between mice and humans. When using murine models to extrapolate human aging, it may be advantageous to focus on aging phenomena observed in both species. In conclusion, although mouse models offer significant insights, selecting appropriate biomarkers is crucial for translating findings to human aging.

被引量：- 发表：1970

Making blood: Mechanisms of early hematopoietic development.

被引量：- 发表：1970