MedNexus
2025年 · 第07卷第02期
MedNexus
The erythroblastic island (EBI) is a multicellular structure defined by the presence of 1 or 2 central macrophages surrounded by at least 3 erythroblasts. EBIs were initially proposed as a specialized microenvironment exclusively for erythroid terminal differentiation. Recent advancements in techniques such as lineage tracing mouse models, imaging flow cytometry, and single-cell RNA sequencing, accumulating evidence has provided novel insights that challenge this conventional view. Notably, the erythropoietin receptor has been identified as a novel marker for EBI macrophages. Additionally, neutrophils have been identified as novel cellular components of EBIs, raising the intriguing hypothesis that EBIs may support other hematopoietic lineage cells as well. Beyond the diverse cellular components of various hematopoietic lineages, even within the erythroid lineage, an immune-prone erythroblast subpopulation has been reported, although it remains unclear whether and how these immune-prone erythroblasts mature in EBIs. These observations indicate that EBIs are a heterogeneous population. In this review, we summarize the most recent findings on EBIs, discuss their potential immune functions, and provide a perspective for future investigations.
Hematological malignancies encompass a diverse range of blood-related cancers characterized by abnormal blood cell production. These cancers, classified by the World Health Organization based on lineage, cell origin, and progression, provide a more comprehensive framework for understanding cancer biology. This classification has significantly advanced cancer research, particularly in genetic analyses for diagnosis and treatment. Despite recent clinical improvements, challenges, such as relapse, resistance, and high mortality, remain unresolved. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a protein that induces apoptosis in cancer cells without affecting normal cells, has emerged as a promising therapeutic target. However, its clinical efficacy is limited by factors, such as tumor heterogeneity and resistance to TRAIL signaling. This review examines the mechanisms of TRAIL in hematological malignancies, factors contributing to resistance, and the current state of preclinical and clinical research, highlighting potential strategies to enhance TRAIL-based therapies in blood cancers.
Acute leukemia (AL), which includes acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), is a hematological malignancy characterized by the uncontrolled proliferation of immature myeloid or lymphoid cells. Allogeneic stem cell transplantation (ASCT) remains a therapeutic option for patients with AL. Determination of transplantation indications is a key step in successful ASCT and in curing patients. Currently, the measurable residual disease (MRD) is used as a biomarker for response evaluation, relapse prediction, preemptive therapy, and post-remission treatment selection. In this review, we discuss the advantages and disadvantages of these techniques for MRD detection. We focused mainly on the residual disease-directed selection of transplant indications for patients with either AML or ALL and provided expert opinions in these settings. We also discuss the challenges associated with transplantation indications and propose expert opinions and future directions for the selection of indications for transplantation.
Primary vitreoretinal lymphoma (PVRL), a rare subtype of primary central nervous system lymphoma (PCNSL), can lead to permanent vision loss and central nervous system (CNS) involvement, resulting in a poor prognosis. PVRL often masquerades as uveitis, and its partial response to topical corticosteroids further complicates the diagnosis. The gold standard for diagnosis is cytological analysis; however, owing to its low sensitivity, cytokine profiling and genetic testing may serve as supplementary diagnostic tools. There is no universally accepted consensus regarding PVRL treatment protocols. Combined systemic high-dose intravenous methotrexate (MTX) and intravitreal therapy may help manage bilateral ocular lesions, although this combination’s ability to delay CNS relapse remains controversial. For relapsed or refractory (R/R) PVRL patients aged <60 years, intensive consolidation chemotherapy followed by autologous stem cell transplantation may be considered. Novel targeted therapies such as ibrutinib and lenalidomide have demonstrated efficacy in R/R cases. Large-scale multicenter prospective studies are urgently needed to determine optimal treatment strategies.
Lineage switch is a rare phenomenon in which acute myeloid leukemia (AML) transforms into acute lymphoblastic leukemia (ALL) and vice versa, sharing the same clonal origin. It is more common for AML to relapse as ALL. Cytogenetics, microenvironment, and preceding therapies are associated with lineage switch. Since the etiology of lineage switch is unclear, presumptions include clonal selection, pluripotent stem cells, and differentiated cell trans-differentiation or re-differentiation. The key point for diagnosing lineage switch is that the relapsed tumor originates from the common cell of the primary leukemia, although it is occasionally derived via clonal evolution. It is very important to distinguish lineage switch from other illnesses, such as secondary leukemia or the blast phase of chronic leukemia. Although direct treatment of the present lineage results in an improved prognosis, the outcome of these patients remains poor, with low survival and rapid progression. Hematopoietic stem cell transplantation can extend survival. Lineage switch risk-adapted management stratification may be beneficial for detecting relapse and more promptly provide suitable therapy. Efficient and toxicity-restricted therapy is being developed to improve the very poor prognosis.
Although changes in mitochondrial morphology consistently associated with the aging of hematopoietic stem cells (HSCs), the specific molecular and cellular mechanisms involved are partially unclear. Live-cell super-resolution (SR) microscopy has been used to identify distinct HSC subsets that characterized by mitochondria unique morphologies and spatial distributions. The integration of SR microscopy with single-cell RNA sequencing enabled the classification of approximately 200 HSCs from young and aged mice into 5 discrete clusters. These clusters displayed molecular profiles that corresponded to the observed mitochondria states. An integrated approach combining RNA biomarker analysis and potential regulon assessment revealed previously unrecognized roles of GDF15 in mediating mitochondrial signals and morphologies that influence HSC fate. Thus, combining SR imaging with a bioinformatics pipeline provides an effective method for identifying key molecular players in specific phases of cellular transition, even with a relatively small dataset.
The triggering receptors expressed on myeloid cells (TREMs) family of cell surface receptors are mainly expressed by myeloid cells. The expression profile of TREM-like 2 (TREML2), a TREM family member, in patients with acute myeloid leukemia (AML) is unknown. In this study, we aimed to elucidate the role of TREML2 in the development of AML. We analyzed the TREML2 expression profile in patients with AML. TREML2 was expressed at lower levels in patients with AML than in healthy individuals. The partial remission (PR) + no remission (NR) group showed lower TREML2 expression levels and a poorer chemotherapy response than that observed in the complete remission group. Overall survival was significantly shorter in the group with low TREML2 expression levels than in the group with high TREML2 expression levels. TREML2 inhibited the proliferation of AML cells and enhanced the sensitivity of AML cells to doxorubicin. Mechanistically, TREML2 reduced C-X-C motif chemokine ligand 10 expression levels by inhibiting the nuclear factor kappa B pathway. Taken together, we demonstrate that TREML2 has diagnostic value as a potential indicator of AML and that upregulation of TREML2 may be a new strategy to overcome doxorubicin resistance for AML treatment.Visual Abstract: http://links.lww.com/BS/A108
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by poor clinical outcomes, frequently exacerbated by mutations in the FMS-like tyrosine kinase 3 (FLT3) gene. Although FLT3 inhibitors (FLT3i) have emerged as promising therapeutic agents, the absence of molecular biomarkers to predict FLT3i response remains a critical limitation in clinical practice. In this study, we performed a comprehensive multi-omics analysis integrating transcriptomic, proteomic, and pharmacogenomic data from the Beat AML cohort, the Cancer Cell Line Encyclopedia (CCLE), and the PXD023201 repository to elucidate the molecular consequences of FLT3 mutations in AML. Our analysis revealed significant differences in RNA and protein expression profiles between FLT3-mutant and wild-type AML cases, with a particularly striking association between FLT3 mutations and immune suppression. We further evaluated the drug sensitivity of FLT3-mutant patients to 3 FDA-approved FLT3i, gilteritinib, midostaurin, and quizartinib, and observed heightened sensitivity in FLT3-mutant cohorts, accompanied by the activation of immune-related pathways in treatment-responsive groups. These findings suggest a potential synergy between FLT3i efficacy and immune activation. Through rigorous bioinformatic analysis, we identified 3 candidate biomarkers: CD36, SASH1, and NIBAN2, associated with FLT3i sensitivity. These biomarkers were consistently upregulated in favorable prognostic subgroups and demonstrated strong correlations with immune activation pathways. The identification of CD36, SASH1, and NIBAN2 as predictive biomarkers offers a novel toolset for stratifying FLT3i response and prognosis.
Acute myeloid leukemia (AML) is characterized by the accumulation of cytogenetic and molecular abnormalities. Isocitrate dehydrogenase 1 and 2 (IDH1/2) mutations occur in 11% to 20% of adults with AML. The outcome of IDH1/2-mutated AML is heterogeneous and affected by co-mutational patterns. We retrospectively analyzed 118 patients with IDH1/2-mutated AML who were retrieved from 1597 patients newly diagnosed with AML and treated with intensive chemotherapy. Univariate analysis revealed the NPM1 mutation was a favorable factor (p = 0.019) for overall survival (OS), whereas the DNMT3A mutation was consistently associated with a poor outcome (3-year OS, 52.0%; 3-year relapse-free survival [RFS], 44.8%; and 3-year cumulative incidence of relapse [CIR], 42.6%). Interestingly, the DNMT3A mutation still identified patients with a poorer prognosis, even when measurable residual disease (MRD) was negative after 2 courses of chemotherapy. In a multivariate regression model, age, DNMT3A mutation and MRD positivity were retained as independent adverse markers for OS, RFS, and CIR. In the absence of the DNMT3A or FLT3-ITD mutations, the NPM1 mutation identified patients with a very favorable OS (3-year OS, 96.3% and 86.3%, respectively). Finally, hematopoietic stem cell transplantation in first complete remission significantly improved RFS (p = 0.015) and there was a trend toward improvement in OS (p = 0.282) for patients with the DNMT3A mutation but it did not benefit 2 subgroups with the IDH1/2+/NPM1+/DNMT3A- and IDH1/2+/NPM1+/FLT3-ITD-genotypes. In summary, this study provides a reference for risk stratification and treatment implications for patients with IDH1/2-mutated AML as well as for comparison with results of IDH inhibitor- or venetoclax-based combination therapy.
The use of cytarabine (Ara-C) in treating acute promyelocytic leukemia (APL) is controversial. This study was conducted to demonstrate the effect of treatment with or without Ara-C on long-term event-free survival (EFS) or overall survival (OS). All patients received all-trans retinoic acid (ATRA) + arsenic trioxide (ATO) induction therapy, followed by the course of idarubicin (IDA) and ATO, then were randomly allocated to 2 groups for consolidation therapy, with patients in the daunorubicin (DNR) group received DNR, in the DNR + Ara-C (DA) group received DNR + Ara-C. Maintenance therapy consisted of oral ATRA, 6-mercaptopurine, and methotrexate for 1.5 years. Thirty patients in DA group and 35 patients in DNR group, all achieved complete remission. At follow-up, there was 1 death and 3 relapses in DNR group, compared to none in DA group. There was no statistically significant difference in EFS (p = 0.140) and OS (p = 0.398) between 2 groups, with EFS being 100% in DA group and 91.4% ± 0.047 in DNR group, and OS being 100% in DA group and 97.1% ± 0.028 in DNR group. Our study found no prognostic significance of Ara-C, this may be related to the small sample size. We still recommend the addition of Ara-C during treatment, which has a more positive impact on early remission and late prognosis of patients.
Langerhans cell histiocytosis (LCH) is a rare disorder that primarily affects children. Considering the intricate clinical presentation of this disease, the identification of specific biomarkers associated with susceptibility to LCH is essential for timely diagnosis and risk stratification. In this study, we examined the skin specimens from pediatric patients with LCH using RNAscope, immunohistochemistry, and sequencing techniques. We observed a notable correlation between elevated CCR6 expression in pathological tissues and LCH risk classification. Therefore, CCR6 expression may serve as an independent predictor of risk in clinical cases of LCH. Furthermore, the frequency of BRAF V600E mutations correlated with risk stratification. We discovered new mutations-H119Y and R108Q—in MAP2K1 in specimens with BRAF V600E mutations. Moreover, CCR6-positive tumors may exhibit an enhanced recruitment of lymphocytes expressing high CCR7 levels.
The combined analysis of dual diseases can provide new insights into pathogenic mechanisms, identify novel biomarkers, and develop targeted therapeutic strategies. Polycythemia vera (PV) is a chronic myeloproliferative neoplasm associated with a risk of acute myeloid leukemia (AML) transformation. However, the chronic nature of disease transformation complicates longitudinal high-throughput sequencing studies of patients with PV before and after AML transformation. This study aimed to develop a diagnostic model for malignant transformation of chronic proliferative diseases, addressing the challenges of early detection and intervention. Integrated public datasets of PV and AML were analyzed to identify differentially expressed genes (DEGs) and construct a weighted correlation network. Machine-learning algorithms screen genes for potential biomarkers, leading to the development of diagnostic models. Clinical specimens were collected to validate gene expression. cMAP and molecular docking predicted potential drugs. In vitro experiments were performed to assess drug efficacy in PV and AML cells. CIBERSORT and single-cell RNA-sequencing (scRNA-seq) analyses were used to explore the impact of hub genes on the tumor microenvironment. We identified 24 genes shared between PV and AML, which were enriched in immune-related pathways. Lactoferrin (LTF) and G protein-coupled receptor 65 (GPR65) were integrated into a nomogram with a robust predictive power. The predicted drug vemurafenib inhibited proliferation and increased apoptosis in PV and AML cells. TME analysis has linked these biomarkers to macrophages. Clinical samples were used to confirm LTF and GPR65 expression levels. We identified shared genes between PV and AML and developed a diagnostic nomogram that offers a novel avenue for the diagnosis and clinical management of AML-related PV.
High recurrence is a major challenge in treating T-lymphoblastic lymphoma (T-LBL). Allogeneic (allo-) or autologous (auto-) stem cell transplantation (SCT) is recommended to reduce relapse, though the optimal choice remains unclear. This study retrospectively analyzed outcomes in T-LBL patients undergoing SCT, with 44 patients receiving allo-SCT and 25 receiving auto-SCT. After a median follow-up of 115 months, the 5-year cumulative incidence of relapse (CIR) was 30.4% overall, 28.7% for allo-SCT, and 37.7% for auto-SCT (p = 0.660). Five-year overall survival (OS) was 68.2% for allo-SCT and 64.0% for auto-SCT; progression-free survival (PFS) was 68.2% and 64.0%, respectively (p = 0.580, 0.940). Patients with age-adjusted international prognostic index (aaIPI) ≥3 had a significantly higher relapse rate in the auto-SCT group (p = 0.022). Univariate analysis identified male sex, aaIPI ≥3, non-CR at cycle 4, and non-CR1 at SCT as adverse prognostic factors. Allo-SCT may benefit patients with high aaIPI.
Studies have shown that microRNAs (miRNAs) in red blood cells (RBCs) contribute most of the miRNAs in whole blood, and miRNAs in RBCs are closely related to storage lesions in vitro. However, the role of miRNAs in the process of RBC senescence in vivo remains unclear. We conducted a comprehensive miRNA expression analysis of RBCs collected from enriched mature RBCs in five density layers. The results showed that the type and number of RBC miRNAs changed with the aging of RBCs, the expression levels of 10 RBC miRNAs decreased markedly at the early stage of RBC aging and the levels of 5 RBC miRNAs increased significantly at the terminal stage of RBC senescence. The analysis identified 32 miRNAs whose changes in expression levels were correlated with the two selected aging indexes—pyruvate kinase (PK) activity and RBC indices. The differential expression amounts of the two selected miRNAs (miR-22-3p and miR-144-3p) were confirmed by real-time polymerase chain reaction (PCR) analysis. A bioinformatics analysis identified the potential targets and biological functions of these miRNAs. The experiment of miR-22-3p in the human erythroblast cell line K562 confirmed its negative effects on PK levels. Overall, our research demonstrates, for the first time, that changes in the expression levels of miRNAs during the RBC aging process, and RBC miRNAs thus have the potential to serve as markers of RBC aging in vivo. In addition, the expression of miR-22-3p may regulate RBC senescence by inhibiting PK levels.
致编辑：
致编辑：
NUP98重排（NUP98r）的血液恶性肿瘤因其独特的临床病理学特征而被纳入2022年欧洲白血病网（ELN）分类、2022年世界卫生组织（世卫组织）分类和国际共识分类中。
坚果中线癌家族成员1（坚果1)已知融合主要与低分化和侵袭性癌相关，主要影响儿童和年轻人的中线结构。近日，坚果1融合已经被鉴定为各种恶性肿瘤，包括血液恶性肿瘤。
脐带血（CB）作为含有造血干细胞（HSC）和成熟免疫细胞的医学资源发挥着重要作用。脐带血移植（CBT）治疗造血障碍提供了几个优点，包括早期开始治疗的能力，即使在人类白细胞抗原（HLA）错配的接受者中也降低了严重慢性移植物抗宿主病的发生率，从而导致更好的移植后生活质量，以及与其他移植方法相比更强的抗肿瘤免疫应答，从而降低了移植后复发的风险。
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