Blood Research最新文献

Leukemia treatment faces persistent challenges, including chemotherapy resistance and relapse, highlighting macrophage polarization in the tumor microenvironment (TME) as a therapeutic target. Macrophages dynamically shift between antitumor M1 and protumor M2 phenotypes, with M2-polarized tumor-associated macrophages (TAMs) dominating leukemia TMEs. These cells secrete IL-10 and TGF-β, fostering immune evasion, angiogenesis, and leukemia stem cell (LSC) survival. In AML, M2 TAMs correlate with poor prognosis and chemoresistance via CSF-1/IL-10 signaling. Polarization is regulated by transcription factors (STAT6, PPARγ, KLF4), hypoxia, and metabolic reprogramming. Therapeutic strategies focus on: (1) M2 depletion (anti-CD163/CD206 antibodies); (2) Pathway inhibition (CCL2/CCR2 or IL-4/STAT6 blockade); (3) Metabolic modulation (glycolysis/OXPHOS targeting); and (4) Phagocytosis enhancement (CD47-SIRPα blockade, HDAC6 inhibition). Preclinical studies demonstrate CSF-1R inhibitors (e.g., pexidartinib) disrupt LSC-TAM crosstalk, while CAR-M therapy synergizes with phagocytosis-promoting agents. Despite challenges, macrophage-targeted therapies offer transformative potential by remodeling the TME, overcoming resistance, and augmenting immunotherapy. This review outlines mechanistic insights and translational strategies to harness macrophage plasticity for leukemia treatment.

Background: The role of Ras-related dexamethasone-induced 1 (RASD1) in multiple myeloma (MM) pathogenesis remains unclear. This study investigated the expression profile, clinical significance, and epigenetic regulation of RASD1 in MM.

Methods: Bone marrow samples were collected from 26 newly diagnosed patients with MM and 8 healthy controls. RASD1 messenger RNA (mRNA) and protein expression were analyzed using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry, respectively. DNA methylation status was assessed via methylation-specific PCR (MSP). The U266 MM cell line was treated with the demethylating agent decitabine (DAC) to evaluate its effects on RASD1 expression and apoptosis.

Results: RASD1 mRNA and protein expression were significantly downregulated in patients with MM compared to healthy controls (P < 0.001). Low RASD1 mRNA levels correlated significantly with advanced DS stage, anemia, hypercalcemia, and elevated M-protein concentrations (P < 0.05). The receiver operating characteristic curve indicated that RASD1 mRNA expression was a robust discriminator between patients with MM and healthy individuals (area under the curve = 0.882, sensitivity = 100%, specificity = 75%). MSP analysis revealed RASD1 promoter hypermethylation in patients with MM, whereas controls exhibited hypomethylation. Treatment of U266 cells with DAC restored RASD1 expression and significantly increased apoptosis compared with controls (12.08% vs. 5.04%, P < 0.01).

Conclusion: RASD1 is frequently silenced in MM through promoter hypermethylation. This epigenetic inactivation is associated with adverse clinical features and enhanced cell survival, supporting a tumor suppressor role for RASD1 in MM pathogenesis.

This review examines the role of METTL3, a core RNA methyltransferase, in therapeutic resistance in acute myeloid leukemia (AML) and discusses emerging strategies to address this challenge. METTL3 regulates N⁶-methyladenosine (m⁶A) modifications on transcripts involved in key cellular processes, including apoptosis (BCL2, MCL1), metabolism (PGC-1α, CSRP1), proliferation (MYC), autophagy (FOXO3), and bone marrow microenvironmental interactions (ITGA4, AKT1). These modifications enhance the stability and translation of resistance-associated genes, supporting leukemic cell survival under treatment pressure. Pharmacological targeting of METTL3 has shown efficacy in preclinical AML models. Inhibitors such as STM2457, METTL3-directed PROTACs, and rational drug combinations with agents including venetoclax, anthracyclines, and ATRA, have reversed resistance phenotypes and impaired leukemic cell fitness. Beyond canonical resistance mechanisms, METTL3 also regulates noncoding RNAs, autophagy, and metabolic-epigenetic crosstalk, including histone lactylation, linking epitranscriptomic regulation to broader resistance pathways. By integrating molecular, cellular, and microenvironmental evidence, this review underscores METTL3 as a central driver of drug resistance and a promising therapeutic target in relapsed or refractory AML. Unlike previous summaries, it highlights the convergence of METTL3-mediated m⁶A modifications with noncoding RNA regulation, autophagy, and niche adaptation, and critically evaluates emerging therapeutic approaches, including catalytic inhibitors, PROTACs, and natural compounds.

EZR (Easy R) is a statistical software package that is freely available on our website ( https://www.jichi.ac.jp/usr/hema/EZR/statmed.html ) and can be used on both Windows (Microsoft Corporation, USA) and macOS (Apple, USA) systems. EZR is built on R and R Commander and offers a range of statistical functions, including survival analyses with competing risks or time-dependent covariates, receiver operating characteristic curve analyses, meta-analyses, and sample size calculations, all accessible through a point-and-click graphical interface. A previous report that described the installation and basic operation of EZR ("Investigation of the freely available easy-to-use software 'EZR' for medical statistics", Bone Marrow Transplant, 2013) has been cited in more than 14,000 scientific papers as of November 2025. This report describes the procedures for performing propensity score (PS) analysis, including PS matching and inverse probability weighting, and compares these approaches with conventional multivariate analyses.

Purpose: Previous studies have been inconsistent concerning the associations of smoking and alcohol consumption with the prognosis of diffuse large B-cell lymphoma (DLBCL). This study aimed to investigate the associations of smoking and drinking status with overall survival (OS) in male patients with DLBCL.

Methods: A total of 371 male patients with newly diagnosed DLBCL were retrospectively enrolled from eight medical centers. Smoking and drinking status were assessed as binary variables (yes or no). Inverse probability of treatment weighting (IPTW) based on propensity scores was applied to adjust for potential confounders. Kaplan-Meier survival analysis and Cox proportional hazards models were used to assess associations.

Results: Overall, 17.3% (n = 64) were smokers, and 12.7% (n = 47) reported alcohol consumption. After weighting, smoking was not associated with OS (HR = 1.192, 95% CI: 0.546-2.605, P = 0.665), nor was alcohol consumption (HR = 0.864, 95% CI: 0.174-4.288, P = 0.808). Subgroup analyses showed interactions between smoking and age (P for interaction = 0.003), and between drinking and EBV DNA status (P for interaction = 0.004). Sensitivity analyses using complete-case data and three-category exposure variables yielded consistent findings.

Conclusions: In this multicenter cohort of male DLBCL patients, neither smoking nor alcohol consumption was associated with the prognosis of DLBCL. Among EBV-positive patients, alcohol use was associated with a trend toward poorer prognosis, highlighting the need for further research.

Background: Platelets are hypothesized to participate in the pathogenesis of Crohn's disease (CD) by interacting with other inflammatory cells such as natural killer (NK) cells. In this study, we aimed to evaluate the effects of platelet-NK cell interactions, both in vitro and in vivo, along with the corresponding mechanisms.

Methods: Clinical data were collected from patients with CD and IL-10 receptor alpha (IL-10RA) mutations, with the control group being comprised of patients with functional abdominal pain. Platelets and NK cells from the patients' colon tissues were immunostained. Dextran sulfate sodium (DSS)-induced colitis models using wild type (WT) and Stimulator of Interferon Genes knockout (STING^-/-) mice were evaluated. Both purified CD41⁺ and CD41^-NK cells were cultured with IL-2 and STING inhibitor C-176 to determine in vitro cell proliferation and Type 3 (T3) cytokine expression. Flow cytometry, enzyme-linked immunosorbent assays, and RT-PCR were used to assess the expression of CD41, IL-17, and adhesion-related molecules in mouse and human NK cells.

Results: Circulating and intestinal platelets were higher in patients with IL-10RA mutations compared to CD patients and correlated positively with serum cytokines, fecal calprotectin (FCP), and blood NK cells. Gut inflammation and T3 cytokine expression in NK cells were significantly lower in STING^-/- mice compared to WT mice. Platelet-adherent NK cells showed significant proliferation and enhanced T3 cytokine expression, whereas STING inhibition markedly suppressed platelet adhesion, cell proliferation, and T3 cytokine expression. The naïve lung tissue of mice also displayed similar platelet-NK cell interactions. Platelet adhesion on NK cells led to higher CD24 expression compared to CD41^-NK cells and we observed relatively higher CD24 in the NK cells from patients with IL-10RA mutations compared to patients with CD.

Conclusions: Spontaneous platelet adhesion via STING signaling potentiates NK cell proinflammatory response in CD.

Purpose: Myelodysplastic syndromes/neoplasms (MDS) represent a heterogeneous group of clonal hematopoietic disorders with variable prognosis. While several risk models exist, the prognostic role of immune-related biomarkers remains unclear. This study aimed to determine whether the lymphocyte-to-monocyte (L/M) ratio at diagnosis serves as an independent prognostic factor in MDS and to explore its biological correlates.

Methods: A retrospective analysis of 554 patients with primary MDS diagnosed at the National Taiwan University Hospital was conducted. Patients were stratified by an L/M ratio cutoff of 1.5, determined by maximally selected rank statistics. Clinical, cytogenetic, and mutational profiles were assessed. Survival outcomes were analyzed using Kaplan-Meier methods and multivariable Cox regression incorporating IPSS-R, IPSS-M, and WHO-2022/ICC classifications. RNA sequencing was performed on diagnostic bone marrow samples to evaluate transcriptomic differences between groups.

Results: Patients with L/M ratio > 1.5 were younger, had lower platelet counts, more advanced subtypes, and higher frequencies of STAG2 and U2AF1 mutations. Elevated L/M ratio was significantly associated with inferior leukemia-free and overall survival, independent of established prognostic models. Adverse prognostic effects were mitigated by allogeneic hematopoietic stem cell transplantation but not by hypomethylating agents. Transcriptomic analysis revealed downregulation of inflammatory pathways (IL-2-STAT5, IL6-JAK-STAT3, interferon responses) and the p53 pathway, along with enrichment of MYC targets in the high L/M group.

Conclusion: An elevated L/M ratio is an independent and readily available biomarker that predicts poor outcomes in MDS. Integration of this parameter into existing risk models may refine prognostication and guide treatment intensity. Transcriptomic findings suggest immune suppression and p53 deregulation underlie its adverse impact, highlighting potential therapeutic avenues.

Purpose: The incidence of chronic lymphocytic leukemia (CLL) is rising in Korea; however, clinical management often diverges from international guidelines due to limited clinical experience, restricted access to diagnostics, and delayed reimbursement for novel agents. This study aimed to assess Korean hematologists' awareness, clinical practices, and perceived barriers in the management of CLL.

Methods: A nationwide, web-based survey was conducted between May 29 and June 19, 2023, targeting hematologists registered with the Korean Society of Hematology who were actively treating patients with CLL. The 15-item questionnaire addressed clinical experience, treatment approaches, use of bruton tyrosine kinase inhibitor (BTKi), awareness and application of prognostic tools, access to molecular diagnostics, reimbursement priorities, and perceived need for national clinical guidelines. A total of 89 hematologists completed the survey.

Results: Patient caseloads varied, with 41.6% of physicians managing 10-19 patients over the prior six months. Treatment patterns were heterogeneous, and undertreatment was commonly attributed to patient refusal (33.7%) and advanced age (10.1%). Despite reimbursement limitations, 15.7% reported prescribing BTKis in ≥ 40% of their patients, although adverse events and intolerance were frequently cited challenges. Awareness of prognostic indices was high, yet their implementation was inconsistent. Access to essential molecular diagnostics was suboptimal; 53% lacking Immunoglobulin heavy-chain variable region gene (IGHV) mutation testing and 43% lacked measurable residual disease (MRD) assessment, whereas TP53 testing was broadly available. Nearly half of the respondents prioritized second-generation BTKis for first-line reimbursement, and 94.4% endorsed the need for Korean-specific clinical guidelines.

Conclusion: This survey highlights gaps between international recommendations and Korean real-world practice, emphasizing the need for improved diagnostic availability, timely reimbursement of targeted agents, and development of Korea-specific clinical guidelines tailored to the Korean context.