Yewei Wang

Background: Acute promyelocytic leukemia (APL) has become a highly curable malignancy with the advent of targeted therapies. However, early death (ED), predominantly caused by severe hemorrhagic complications, continues to be the most significant obstacle to achieving high survival rates in real-world clinical practice, where outcomes often lag behind those reported in controlled trials. Aims: This retrospective study aimed to identify the key clinical and laboratory factors associated with ED and overall survival (OS) in a cohort of newly diagnosed APL patients. The study also sought to evaluate the impact of current supportive care strategies and identify opportunities for improved management. Methods: This single-center, retrospective analysis included 132 patients newly diagnosed with APL between June 2017 and January 2023. Data on demographics, baseline laboratory values, immunophenotyping, treatment, and outcomes were collected. Univariate and multivariate logistic regression analyses were used to identify independent predictors of ED, while Kaplan-Meier and Cox regression models were used to assess survival outcomes. Results: The ED rate was 12.88% (17 patients), with hemorrhage being the primary cause. Multivariate analysis identified three independent risk factors for ED: a high white blood cell (WBC) count (>201 × 10 ⁹ /L), prolonged prothrombin time (PT), and CD2 positivity. While severe thrombocytopenia was common, it was not an independent predictor, likely due to an aggressive platelet transfusion policy. Elevated lactate dehydrogenase (LDH) levels were significantly associated with poorer OS. Furthermore, all relapses in the high-risk group involved the central nervous system (CNS). Conclusions: This study found that high initial WBC count, prolonged PT, and CD2 positivity are critical independent predictors of ED in APL. The findings underscore the necessity of prompt diagnosis, risk-adapted therapy, and comprehensive multidisciplinary care, including aggressive management of coagulopathy. Enhanced CNS prophylaxis should be considered for high-risk patients to prevent relapse.

Aims: Acute promyelocytic leukemia (APL) progresses quickly and often leads to early hemorrhagic death. Treatment with all-trans retinoic acid (ATRA) promotes differentiation of APL cells and clinical remission, making APL a potentially curable malignancy. Understanding how ATRA works may lead to new treatments for other types of leukemia. Long non-coding RNA NEAT1 has been implicated in the differentiation of APL cells. This study aims to elucidate the specific role of NEAT1 in the granulocytic differentiation of APL. Methods: The influence of NEAT1 on autophagy and PML/RARα degradation was assessed using western blot assays. The impact of NEAT1 on the expression of autophagy-related genes was evaluated through quantitative real-time RT-PCR. Mechanistic insights into the role of NEAT1 in modulating autophagy were supported by RNA immunoprecipitation and RNA pulldown assays. Key findings: Knockdown of NEAT1 suppressed autophagy and attenuated ATRA-induced PML/RARα degradation and granulocytic differentiation of APL cells. Subsequent screening of autophagy-related genes demonstrated that silencing NEAT1 impaired the ATRA-induced upregulation of ATG10 and ATG12. Mechanistic investigations revealed that the RNA-binding protein TAF15 interacted with NEAT1, synergistically stabilizing the mRNA of ATG10 and ATG12. Furthermore, knockdown of NEAT1 impaired the interactions between TAF15 and the mRNAs of ATG10 and ATG12, thereby compromising their mRNA stability. Significance: Our study elucidates the critical role of NEAT1-mediated autophagy in the differentiation of APL cells and delineates the molecular mechanism by which upregulation of NEAT1 enhances autophagy. Specifically, NEAT1 binds to the RNA-binding protein TAF15, which in turn stabilizes the mRNA of both ATG10 and ATG12.

Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8 ⁺ T cells during GVHD, alloreactive CD4 ⁺ T cell clusters were preferentially expanded. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T cell exhaustion. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4 ⁺ T cells (T _CM ) with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to posttransplant cyclophosphamide (PT-Cy), CSA was ineffective in eliminating IL-17A–secreting alloreactive T cell clones that play an important role in the pathogenesis of cGVHD. Collectively, we have shown that, although CNIs attenuate aGVHD, they paradoxically rescue alloantigen-specific T _CM , especially within the CD4 ⁺ compartment in lymphoid and GVHD target tissues, thus predisposing patients to cGVHD. These data provide further evidence to caution against CNI-based immune suppression without concurrent approaches that eliminate alloreactive T cell clones.

Graphics are widely used to provide summarization of complex data in scientific publications. Although there are many tools available for drawing graphics, their use is limited by programming skills, costs, and platform specificities. Here, we presented a freely accessible easy-to-use web server named SRplot that integrated more than a hundred of commonly used data visualization and graphing functions together. It can be run easily using all Web browsers and there are no strong requirements on the computing power of users’ machines. With a user-friendly graphical interface, users can simply paste the contents of the input file into the text box according to the defined file format. Modification operations can be easily performed, and graphs can be generated in real-time. The resulting graphs can be easily downloaded in bitmap (PNG or TIFF) or vector (PDF or SVG) format in publication quality. The website is updated promptly and continuously. Functions in SRplot have been improved, optimized and updated depend on feedback and suggestions from users. The graphs prepared with SRplot have been featured in more than five hundred peer-reviewed publications. The SRplot web server is now freely available at http://www.bioinformatics.com.cn/SRplot.

Uncontrolled proliferation is the hallmark of cancer cells. Previous studies mainly focused on the role of protein-coding genes in cancer cell proliferation. Emerging evidence showed that long non-coding RNAs (lncRNAs) also play critical roles in cancer cell proliferation and growth. LncRNA KCNQ1OT1 is found to contribute to carcinogenesis, but its role in acute promyelocytic leukemia (APL) is unclear. In this study, by analyzing data from Gene Expression Omnibus, The Cancer Genome Atlas database and our clinical samples, we found that KCNQ1OT1 was selectively highly expressed in APL. Functional assays demonstrated that knockdown of KCNQ1OT1 reduced APL cell proliferation and increased apoptosis. Further evidence showed that KCNQ1OT1 was mainly located in the cytoplasm of APL patient-derived NB4 cells and APL patient bone marrow samples. Mechanistically, KCNQ1OT1 bound to RNA binding protein FUS, and silencing either KCNQ1OT1 or FUS reduced the expression level and stability of MAP3K1 mRNA. Whereas KCNQ1OT1 and FUS did not affect each other. Importantly, knockdown of MAP3K1 impaired APL cell proliferation. Finally, c-Myc transactivated KCNQ1OT1 in APL cells through binding to its promoter while knockdown of c-Myc decreased KCNQ1OT1 expression. Our results not only revealed that c-Myc transactivated KCNQ1OT1 and upregulated KCNQ1OT1 promoted APL cell proliferation, but also demonstrated that KCNQ1OT1 bound to FUS to synergistically stabilize MAP3K1 mRNA, thus facilitating APL cell proliferation. This study established a previously unidentified role of KCNQ1OT1 in the development of APL, and KCNQ1OT1 may serve as a potential therapeutic target for APL.

Better understanding of the transcriptional regulatory network in acute promyelocytic leukemia (APL) cells is critical to illustrate the pathogenesis of other types of acute myeloid leukemia. Previous studies have primarily focused on the retinoic acid signaling pathway and how it is interfered with by promyelocytic leukemia/retinoic acid receptor-α (PML/RARα) fusion protein. However, this hardly explains how APL cells are blocked at the promyelocytic stage. Here, we demonstrated that C/EBPα bound and transactivated the promoter of long non-coding RNA NEAT1, an essential element for terminal differentiation of APL cells, through C/EBP binding sites. More importantly, PML/RARα repressed C/EBPα-mediated transactivation of NEAT1 through binding to NEAT1 promoter. Consistently, mutation of the C/EBP sites or deletion of retinoic acid responsive elements (RAREs) and RARE half motifs abrogated the PML/RARα-mediated repression. Moreover, silencing of C/EBPα attenuated ATRA-induced NEAT1 upregulation and APL cell differentiation. Finally, simultaneous knockdown of C/EBPα and C/EBPβ reduces ATRA-induced upregulation of C/EBPε and dramatically impaired NEAT1 activation and APL cell differentiation. In sum, C/EBPα binds and transactivates NEAT1 whereas PML/RARα represses this process. This study describes an essential role for C/EBPα in PML/RARα-mediated repression of NEAT1 and suggests that PML/RARα could contribute to the pathogenesis of APL through suppressing C/EBPα targets.

Acute leukemia (AL) occurring in pregnancy is extremely rare, and its treatment is a clinical dilemma.We retrospectively reviewed the medical records of our hospital from 2010 to 2019.Twenty-one pa...

Circular RNAs (circRNAs) are a class of newly identified noncoding RNA and are considered as a new feature of eukaryotic gene expression. Hundreds of thousands of endogenous circRNAs have been found in mammalian cells, which we knew little before. CircRNAs are covalently closed, circular RNA molecules that typically comprise exonic sequences and are spliced at canonical splice sites. Researchers with RNA-Seq technology have identified that the expression of circRNAs is developmentally regulated, tissue- and cell-type specific. Like long noncoding RNAs (lncRNAs), circRNAs are becoming a new research hotspot in the RNA field, and aberrant expression of circRNAs could contribute to carcinogenesis. Recent studies have demonstrated that circRNAs play important roles in the development, maintenance, and progression of leukemia. Herein, we describe the biologic characteristics and functions of circRNAs, with a focus on circRNAs that play essential roles in leukemia.

GTF2I-RARA is a newly identified RARA fusion gene in variant acute promyelocytic leukemia (APL) patients with t(7;17)(q11;q21). Clinical manifestation in the patient showed that it is a sort of ATRA-insensitive oncogene and is different from the classic PML-RARA in terms of therapeutic reaction. To reveal the functional characteristics and regulating mechanism of the GTF2I-RARA fusion gene, we established a GTF2I-RARA-transfected HL60 cell model and examined its sensitivity to ATRA by western blot, MTT assay, flow cytometry, and Wright-Giemsa staining. Coimmunoprecipitation and confocal microscopy were used to examine the binding of GTF2I-RARA and transcriptional corepressors. We also performed ChIP-seq to search for potential target genes. Immunoprecipitation, ubiquitination assay, western blot, luciferase assay, and real-time PCR were used to analyze the effects of RNF8 on RARA. Flow cytometry and Wright-Giemsa staining were used to study the effect of MG132 and ATRA on the GTF2I-RARA-transfected HL60 cell model. We confirmed resistance of GTF2I-RARA to ATRA. Compared with PML-RARA, GTF2I-RARA has a higher affinity to HDAC3 under ATRA treatment. Using the ChIP-sequencing approach, we identified 221 GTF2I-RARA binding sites in model cells and found that the RING finger protein 8 (RNF8) is a target gene of GTF2I-RARA. RNF8 participates in disease progression and therapy resistance in APL with the GTF2I-RARA transcript. Elevated RNF8 expression promotes the interaction between RARA and RNF8 and induces RARA Lys-48 linkage ubiquitylation and degradation, resulting in attenuated transcriptional activation of RARA. Our results suggest that RNF8 is a key GTF2I-RARA downstream event. Using the combination of MG132 and ATRA to treat GTF2I-RARA-HL60 cells, a synergistic effect leading to GTF2I-RARA-HL60 cell differentiation was confirmed. Taken together, the targeting of RNF8 may be an alternative choice for treatment in variant APL with GTF2I-RARA fusion.