Hematology最新文献

Objectives: Chronic myeloid leukemia (CML), a clonal malignant disease arising from the BCR-ABL fusion gene, presents significant therapeutic challenges, particularly in chemotherapy resistance. The role of METTL14, a key m6A methyltransferase, is implicated in cancer biology, but its role in CML remains unclear.

Methods: Peripheral blood mononuclear cells (PBMCs) and CML cell lines (K562 and K562/G01) were conducted in vitro studies. mRNA levels were quantified by quantitative PCR (qPCR), and protein expressions were assessed by Western Blotting. Cell viability and apoptosis were measured using the CCK-8 and flow cytometry, respectively. Drug resistance was evaluated by determining the half-maximal inhibitory concentration (IC50). m6A levels were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and modification sites were predicted by SRAMP and confirmed with a SELECT detection assay. Gene interactions were validated through luciferase assays.

Results: METTL14 expression was significantly elevated in imatinib-resistant CML patients (P=0.005) and K562/G01 cells (P=0.01), correlating with increased m6A modification levels (P=0.032). Overexpression of METTL14 enhanced m6A methylation, promoted cell proliferation, inhibited apoptosis, and increased imatinib resistance in CML cells. Conversely, METTL14 silencing reduced m6A levels, induced G0/G1 arrest, and enhanced apoptosis (P=0.01). Mechanistically, the luciferase assay results demonstrated that METTL14-mediated m6A modification at the A1001 site of Bcl-x mRNA facilitated HNRNPC-dependent splicing. Consequently, this modification results in shifting Bcl-xS to Bcl-xL and inactivating the BCL-2/BAX/Caspase-3 pathway.

Conclusion: METTL14-driven m6A modification regulates the splicing pattern of Bcl-x, and may facilitate the progression of CML. Keywords: CML, METTL14, N6-methyladenine, Bcl-x, Alternative splicing, resistance, imatinib, progression.

Objective: To summarize the clinical characteristics, treatment outcomes, and prognosis of pregnant patients with hemophagocytic lymphohistiocytosis (HLH), and to evaluate the efficacy of chemotherapy regimens containing etoposide (VP16) in these patients and their impact on survival outcomes.

Methods: A retrospective analysis was performed on 41 pregnant HLH patients admitted to our hospital between April 2015 and March 2024, focusing on clinical features, treatment strategies, and prognostic factors.

Results: Among the 41 cases, 29 developed HLH during pregnancy and 12 postpartum. Etiologies included malignancy-related HLH (5 cases), Epstein-Barr virus (EBV)-related HLH (5 cases), rheumatologic disease-related HLH (2 cases), and pregnancy-related HLH (29 cases, defined as no comorbid HLH-related etiologies except pregnancy). In pregnancy-related HLH patients presenting during gestation, the 2-week overall response rate (ORR) was significantly higher in those receiving VP16-containing induction chemotherapy compared to glucocorticoids-only induction therapy (P = 0.011). Multivariate analysis identified the interval from symptom onset to VP16 initiation as an independent prognostic factor for pregnancy-related HLH (P = 0.025). Survival analysis revealed improved survival in patients who received VP16 within 7 weeks of onset versus those treated after 7 weeks (P = 0.044).

Discussion and conclusion: HLH in pregnancy progresses rapidly. Early administration of VP16-containing chemotherapy significantly improves ORR and survival outcomes, particularly in pregnancy-related HLH.

In this retrospective case-control study involving 424 pediatric patients diagnosed with Pediatric Acute Lymphoblastic Leukemia (ALL), the investigation focused on analyzing the clinical characteristics and prognosis associated with the Cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/2B) gene. Treatment and evaluation followed the South China Children's Leukemia Group-ALL-2016 protocol (SCCLG-ALL-2016). Among the cohort, 92 patients (21.7%) exhibited CDKN2A/2B gene deletions, with 11.1% homozygous and 10.6% heterozygous deletions. Notably, ALL patients that do have CDKN2A/2B gene deletions tended to present at an older age (P = 0.001), demonstrate hepatosplenomegaly on palpation (P < 0.001), and exhibit a higher incidence of Central nervous system leukemia (CNSL) (P = 0.037) and T-ALL (P = 0.007). A significant correlation was observed between ALL that does have CDKN2A/2B gene deletions and ETV6::RUNX1-positive (8.7% vs. 19.3%, P = 0.017) and IKZF1 gene deletions (20.7% vs. 8.4%, P = 0.001). Survival analysis of 392 patients revealed no significant differences in 5-year relapse, Overall survival (OS), or Event-free survival (EFS) between ALL that does/ does not have CDKN2A/2B gene deletions. Subgroup analysis highlighted poorer prognosis among hepatosplenomegaly patients in the CDKN2A/2B gene deletion group, with a 5-year EFS of 81.8%, 95%CI (0.695-0.963), P = 0.05. Hepatosplenomegaly emerged as the most significant prognostic factor for EFS [HR = 2.306, 95%CI (1.192-4.461), P = 0.013]. Cox regression analyses identified covariates influencing prognosis, ALL with the CDKN2A/2B gene showing no significant impact on outcomes. In conclusion, while ALL that does have CDKN2A/2B gene deletions is associated with certain clinical characteristics and genetic aberrations, they did not significantly impact OS or EFS. Furthermore, subgroup analysis revealed a potential prognostic role of ALL that does have CDKN2A/2B deletions presenting with hepatosplenomegaly on palpation, emphasizing the importance of comprehensive risk stratification in treatment decision-making for this subgroup.

Background: Relapsed/Refractory (R/R) diffuse large B-cell lymphoma (DLBCL) represents a subgroup with a high incidence and dismal prognosis. Currently, there is a lack of robust models for predicting R/R DLBCL. Therefore, we conducted a retrospective study to identify key determinants to be incorporated into a novel nomogram to enhance the identification of DLBCL patients at elevated risk of refractoriness/recurrence.

Methods: We included 293 newly-diagnosed DLBCL patients from Harbin Medical University Cancer Hospital, collected from 2008-2017. Patients were randomly divided into a training cohort (n = 206) and a validation cohort (n = 87) at a 7:3 ratio. The training cohort underwent univariable analysis to select variables for a binary logistic regression model. These variables were also prioritized using a random forest algorithm. The developed nomogram was evaluated with the receiver-operator characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) for its clinical utility.

Results: Univariable analysis pinpointed several factors significantly associated with refractoriness/recurrence, including pathological subtype, lactate dehydrogenase (LDH), International Prognostic Index (IPI), treatment, absolute lymphocyte count (ALC), lymphocyte/monocyte ratio (LMR), and prognostic nutritional index (PNI). Binary logistic regression highlighted pathological subtype, LDH, treatment, and ALC as key predictors, which were incorporated into the nomogram. The nomogram showed excellent calibration and accuracy in both cohorts, and comparative DCA and ROC analysis demonstrated its superior net benefit and area under the curve (AUC) compared to traditional indexes like IPI, R-IPI, and NCCN-IPI.

Conclusion: This nomogram serves as a valuable tool for predicting the likelihood of refractoriness or recurrence in DLBCL patients.

Objective: Liquid-liquid phase separation (LLPS) may affect the therapeutic sensitivity of multiple myeloma (MM). This study aimed to identify LLPS-related genes with MM prognostic values and to confirm their effects on tumor progression.

Methods: Based on public transcriptomic data, this study screened LLPS- and immune-related genes for MM-derived plasma cells. Subtypes were identified using consensus clustering, followed by comparisons using t-test and survival analysis. Least absolute shrinkage and selection operator was implemented to screen prognostic signatures, and Kaplan-Meier and receiver operator characteristic curves were plotted to assess their prognostic values. After transfected with sh-DDX21, CCK8, flow cytometry, and Transwells were used to observe MM cell proliferation, apoptosis, migration, and invasion.

Results: By overlapping LLPS- and immune-related genes, 103 genes were obtained to cluster MM samples into three subtypes, which had significant differences in survival and immune landscape. Cox regression analysis screened out EZH2 and DDX21 that significantly overexpressed in MM to construct a prognostic model, with superior performance in predicting MM prognostic risks. Notably, subtype2 with more adverse prognosis showed significantly elevated risk scores and was more distributed in groups with high prognostic risk. In vitro experiments confirmed that cell proliferation, invasion, and migration were significantly inhibited in MM.1S cells transfected with sh-DDX21.

Conclusion: LLPS-related EZH2 and DDX21 were novel markers to predict prognostic risk of MM. Among them, DDX21 was experimentally confirmed to promote MM cell proliferation, migration and invasion. These potential prognostic markers could be targeted in future personalized therapeutic strategies for MM, potentially improving patient outcomes.

Objectives: Currently, there is limited understanding regarding the prognostic significance of time to progression (TTP) after first remission in multiple myeloma (MM).

Methods: We conducted a retrospective analysis of clinical data from 209 patients with MM. These patients were categorized into ≤ 6 months, ≤ 12 months, ≤ 24 months, > 24 months, 6-12 months, and 12-24 months subgroups based on TTP.

Results: Patients in ≤ 12 months group exhibited shorter median overall survival (OS) and OS-1 compared to those in ≤ 24 months group (61.73 vs 96.10 months, P = 0.02; 54.00 vs 74.17 months, P = 0.048). ≤ 6 months group exhibited shorter median OS and OS-1 compared to 6-12 months group (33.63 vs 79.60 months, P = 0.022; 19.93 vs 65.17 months, P = 0.015). Patients in 6-12 months group had shorter median OS and OS-1 compared to those in 12-24 months group (79.60 vs 100.43 months, P < 0.001; 65.17 vs 77.17 months, P = 0.012).No significant difference in OS was observed between patients in 12-24 months and > 24 months groups. For patients who experienced progression within 12 or 24 months after remission, undergoing autologous hematopoietic stem cell transplantation (ASCT) after progression conferred a median OS and OS-2 advantage over receiving post-progression chemotherapy. Multivariable analysis confirmed that TTP was an independent predictor for OS in patients with MM.

Conclusion: Patients with MM who experience earlier disease progression within 12 months after remission have a worse prognosis, and post-progression ASCT can improve their survival outcomes.

To investigate the role of ALKBH3 in acute myeloid leukemia (AML), we constructed an animal model of xenotransplantation of AML. Our study demonstrated that ALKBH3-mediated m1A demethylation inhibits ferroptosis in KG-1 cells by increasing ATF4 expression, thus promoting the development of AML. These findings suggest that reducing ALKBH3 expression may be a potential strategy to mitigate AML progression.

Background: Acute myeloid leukemia (AML) is characterized by the unrestrained proliferation of myeloid cells. Studies have shown that ALKBH3 is upregulated in most tumors, but the role of ALKBH3 in AML remains unclear.Methods: In this study, we investigated the function of ALKBH3 in AML cells (KG-1) by immunofluorescence, ELISA, flow cytometry, HE staining, and Western blotting.Results: Our results revealed that ALKBH3 is upregulated in AML and that the downregulation of ALKBH3 inhibited KG-1 cell proliferation and promoted cell apoptosis; at the same time, ALKBH3 upregulated ATF4 expression through m1A demethylation, and the knockdown of ATF4 resulted in increased ferrous iron content; TFR1, ACSL4, and PTGS2 expression; and ROS and MDA levels, whereas SOD and GSH levels and the expression levels of ATF4, SLC7A11, GPX4, and FTH1 decreased in KG-1 cells, thereby promoting ferroptosis. Mechanistically, ALKBH3-mediated m1A demethylation suppressed ferroptosis in KG-1 cells by increasing ATF4 expression, thereby promoting the development of AML.Conclusions: Our study indicated that reducing the expression of ALKBH3 might be a potential target for improving AML symptoms.

Introduction: Cases of warm autoimmune hemolytic anemia (wAIHA) often present with life-threatening levels of hemoglobin requiring red blood cell (RBC) transfusion support.

Aim: This literature review assessed the occurrence, safety, effectiveness, and hospitalization burden of RBC transfusions in the management of patients with wAIHA.

Methods: Electronic databases (Embase, MEDLINE) were searched from inception to December 2021 along with additional searches conducted up to March 2024.

Results: Of the 1478 articles screened, 17 observational studies and reviews were included. These studies demonstrated the use of 1-50 red blood cell transfusions to reach clinically acceptable hemoglobin levels in patients with wAIHA. In general, pre-transfusion hemoglobin levels were 6 g/dL and increased by an average 1.2 g/dL following a transfusion. Approximately 50% of patients with primary or secondary wAIHA suffered relapses. No data was available to distinguish between RBC transfusions used at initial presentation versus during relapse. Five studies found no increase in hemolysis or serious adverse reactions following transfusions and two studies reported mild transfusion-related adverse effects. Limited data was available regarding the hospitalization burden of RBC transfusion. Patients with wAIHA requiring transfusions had a median hospital stay from 15 to 17 days, which is considerably higher than all causes hospitalization of 4.5 days for 2023 U.S.

Conclusion: In patients with wAIHA, data supports wide variability in occurrence, but relative safety and effectiveness of RBC transfusions as supportive therapy. Additional studies are needed to assess the occurrence, safety, and hospitalization burden of RBC transfusions relative to other therapies in chronic relapsing wAIHA.

Background: Dehydrated Hereditary Stomatocytosis (DHS), also known as Hereditary Xerocytosis (HX), is a rare genetic disorder primarily arising from gain-of-function mutations in PIEZO1, which disrupt mechanosensitive ion channels on red blood cell membranes. This dysfunction leads to cellular dehydration and chronic anemia, while DHS/HX cells exhibit increased hypotonic resistance. Interpreting PIEZO1 variants requires integrating clinical findings with specialized knowledge.

Methods: Laboratory tests, whole-genome sequencing, and Sanger sequencing were conducted for clinical phenotyping and identification of disease-causing mutations within the proband and his parents.

Results: The proband was found to have both β-thalassemia trait and Dehydrated Hereditary Stomatocytosis. The proband inherited compound heterozygous mutations in the PIEZO1 gene (c.136G > A and c.6307C > G) from his mother and father, respectively. Additionally, the proband had a heterozygous β-globin gene mutation (c.315 + 2delT) inherited from his father.

Conclusion: Compared to patients with either DHS/HX or β-thalassemia alone, this patient, as a β-thalassemia carrier with suspected Dehydrated Hereditary Stomatocytosis, exhibited highly complex laboratory findings. Genetic testing played a crucial role in diagnosing conditions with overlapping clinical features. Given the increased risk of thromboembolic complications, splenectomy is contraindicated in DHS/HX patients, highlighting the necessity for precise diagnosis of DHS/HX and molecular confirmation of suspected hereditary red blood cell disorders.

Background: The effect of methotrexate (MTX)-related toxicity on childhood acute lymphoblastic leukemia (ALL) is controversial. Hence, this meta-analysis aimed to investigate the association between ABCB1 C3435 T polymorphism- and methotrexate-related toxicity in pediatric acute lymphoblastic leukemia.

Methods: Relevant studies were systematically searched and extracted from multiple databases including PubMed, EMBASE, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang databases up to 1 June, 2024.

Results: A total of 13 articles met the criteria, including 1506 patients. The results showed that ABCB1 C3435 T polymorphism was significantly associated with MTX-induced hepatotoxicity (CT/TT vs. CC: OR: 2.15, 95% CI: 1.40-3.32). There was no significant difference between ABCB1 C3435 T polymorphism and mucositis, myelosuppression, nephrotoxicity, gastrointestinal toxicity in pediatric ALL treated with MTX.

Conclusions: Our meta-analysis suggests that the ABCB1 C3435 T mutation may enhance the MTX-induced hepatotoxicity in childhood acute lymphoblastic leukemia.