Potential applications of ferroptosis inducers and regulatory molecules in hematological malignancy therapy.

Ferroptosis, a novel form of iron-dependent cell death, has emerged as a potential avenue for promoting tumor cell death by causing cell membrane rupture and the accumulation of lipid peroxides (LPO) in the cell. Since its discovery in 2012, extensive research has been conducted to explore the mechanism of ferroptosis inducers, including erastin, sulfasalazine, and sorafenib. These compounds inhibit system XC-, while Ras-selective lethal small molecule 3 (RSL3) and FION2 specifically target GPX4 to promote ferroptosis. Therefore, targeting ferroptosis presents a promising therapeutic approach for malignant tumors. While the study of ferroptosis in solid tumors has made significant progress, there is limited information available on its role in hematological tumors. This review aims to summarize the molecular mechanisms of ferroptosis inducers and discuss their clinical applications in hematological malignancies. Furthermore, the identification of non-coding RNAs (ncRNAs) and genes that regulate key molecules in the ferroptosis pathway could provide new targets and establish a molecular theoretical foundation for exploring novel ferroptosis inducers in hematological malignancies.

Construction and validation of an NAD + metabolism-related lncRNA signature for predicting the prognosis and immune landscape of acute myeloid leukemia.

BACKGROUND: This study aimed to investigate the potential of a NAD+ metabolism-related lncRNA signature as a reliable prognostic biomarker for acute myeloid leukemia (AML). METHODS: Transcriptome profiles and clinical data of AML patients were obtained from The Cancer Genome Atlas (TCGA) database. NAD+ metabolism-related genes (NMRGs) were identified from the KEGG and Reactome databases. Coexpression analysis was used to screen NAD+ metabolism-related lncRNAs. The NAD+ metabolismrelated lncRNA signature was constructed using univariate analysis, LASSO regression, and multivariate analysis. High- and low-risk groups were compared for survival, tumor mutation burden, immune cell infiltration, and response to immunotherapy. Enrichment analysis explored the biological functions. RESULTS: LINC01679, AC079922.2, TRAF3IP2-AS1, and LINC02465 were identified to construct the risk model. The model exhibited good predictive power and outperformed age and gender as an independent prognostic marker. High-risk patients showed poorer survival, distinct TP53 mutations, and altered immune cell infiltration compared to low-risk patients. Additionally, low-risk patients exhibited greater sensitivity to immunotherapy. Enriched biological functions included leukocyte migration and positive regulation of cytokine production. CONCLUSIONS: The NAD+ metabolism-related lncRNA signature shows promise in predicting clinical outcomes for AML patients.

A nomogram based on clinical features and molecular abnormalities for predicting the prognosis of patients with acute myeloid leukemia.

Background: The high clinical and molecular heterogeneity of acute myeloid leukemia (AML) has led to an unsatisfactory clinical prognosis, thus we sought to incorporate both clinical features and molecular abnormalities to construct a new prognostic model. Methods: A database search of the Gene Expression Omnibus (GEO) revealed 238 cases of adult AML. The independent risk factors were assessed using both univariate and multivariate Cox regression, as well as least absolute shrinkage and selection operator (LASSO) regression. The predictive accuracy, discriminatory power and clinical applicability of the nomogram were determined by the consistency index (C-index), calibration curves and decision curve analysis (DCA). In addition, a single-centre cohort of 135 cases was used for external validation. Results: Multivariate Cox regression analysis showed that the independent influences on overall survival (OS) were age, type of disease, DNMT3A, IDH2 and TP53 mutations. The area under the curve (AUC) values for the training set were 0.755, 0.745 and 0.757 at 1, 2 and 3 years respectively; the AUC for the validation set were 0.648, 0.648 and 0.654 at 1, 2 and 3 years; and the AUC for the northwest China set were 0.692, 0.724 and 0.689 at 1, 2 and 3 years. The calibration and DCA indicated good consistency and clinical utility of the nomogram. Finally, younger (age <60 years) and elderly (age ≥60 years) patients were each divided into two risk groups with significantly different survival rates. Conclusions: A nomogram consisting of five risk factors was developed for forecasting the prognosis of AML with guaranteed reliability.

Development and validation of a novel prognosis prediction model for patients with myelodysplastic syndrome.

Background: Somatic mutations are widespread in patients with Myelodysplastic Syndrome (MDS) and are associated with prognosis. However, a practical prognostic model for MDS that incorporates somatic mutations urgently needs to be developed. Methods: A cohort of 201 MDS patients from the Gene Expression Omnibus (GEO) database was used to develop the model, and a single-center cohort of 115 MDS cohorts from Northwest China was used for external validation. Kaplan-Meier analysis was performed to compare the effects of karyotype classifications and gene mutations on the prognosis of MDS patients. Univariate and multivariate Cox regression analyses and Lasso regression were used to screen for key prognostic factors. The shinyapps website was used to create dynamic nomograms with multiple variables. The time-dependent receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA) were used to evaluate the model's discrimination, accuracy and clinical utility. Results: Six risk factors (age, bone morrow blast percentage, ETV6, TP53, EZH2, and ASXL1) were considered as predictor variables in the nomogram. The nomogram showed excellent discrimination, with respective the area under the ROC curve (AUC) values of 0.850, 0.839, 0.933 for the training cohort at 1 year, 3 years and 5 years; 0.715, 0.802 and 0.750 for the testing cohort at 1 year, 3 years and 5 years; and 0.668, 0.646 and 0.731 for the external validation cohort at 1 year, 3 years and 5 years. The calibration curves and decision curve showed that the nomogram had good consistency and clinical practical benefit. Finally, a stratified analysis showed that MDS patients with high risk had worse survival outcomes than patients with low risk. Conclusion: We developed a nomogram containing six risk factors, which provides reliable and objective predictions of prognosis for MDS patients.

The efficacy and adverse events of venetoclax in combination with hypomethylating agents treatment for patients with acute myeloid leukemia and myelodysplastic syndrome: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the efficacy and adverse effects of venetoclax(VEN) in combination with hypomethylating agents(HMAs) in acute myeloid leukemia(AML) or myelodysplastic syndrome(MDS). METHODS: Clinical studies were identified from the Cochrane Library, PubMed, Embase, Google Scholar, and ClinicalTrials.gov. Overall complete remission (CR) and overall response rate (ORR) were used to evaluate the efficacy of VEN in combination with HMAs for AML/MDS, the incidence of the 4 most common grade 3-4 adverse events was used to evaluate safety. RESULTS: We identified 13 studies that included a total of 1059 patients. 7 cohort studies and 5 non-randomized controlled trials(NRCTs) were analyzed by random-effects model, and subgroup analyses showed the pooled overall CR rate of 62% (95% CI 57-67%, I2 = 3%) for the new-diagnosed(ND) AML group, 39% (95% CI 30-48%, I2 = 28%) for relapsed/refractory(R/R)-AML, and 61% (95% CI 50-71%, I2 = 25%) for MDS, respectively. There was only one randomized controlled trial(RCT) that showed a CR rate of 66.4% in the patients who received azacitidine(AZA) plus VEN. A total of 8 studies reported adverse events, with cytopenia and infection being the most common grade 3-4 adverse events. CONCLUSIONS: The addition of VEN to HMAs may provide significant clinical benefit for AML/MDS patients, where response rates are better in MDS and ND-AML than in R/R-AML, but attention should be paid to the possible increased risk of febrile neutropenia.

Leukaemia cutis as a specific skin involvement in chronic myelomonocytic leukaemia and review of the literature: Acknowledgments.

The skin involvement of myeloid leukaemia is conventionally divided into specific malignant lesions and non-specific benign lesions, and these categories are also applicable in chronic myelomonocytic leukaemia (CMML). According to the 2016 World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues, CMML is defined as a myeloid neoplasm with characteristics of myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPNs). As a specific cutaneous sign of extramedullary infiltration, leukaemia cutis (LC) is a rare occurrence in patients with CMML, and only approximately 89 cases have been reported in the literature thus far. The clinical features of LC are varied, and LC in CMML exhibits heterogeneous histopathologic features, with manifestations as cutaneous nodules or papules that are composed of blast cells showing either granulocytic or monocytic differentiation. Skin biopsy and further immunohistochemical examination are essential at the time of diagnosis to evaluate pathological type and determine the clinical course. Generally, once diagnosed as LC in CMML, this unusual skin lesion might be an indicator of transformation to acute myeloid leukaemia (AML) and is associated with a poor prognosis. The main treatment is allogeneic stem cell transplantation (ASCT). Therefore, early diagnosis and accurate identification have important therapeutic and prognostic significance in CMML patients with skin infiltration.

Outcomes of 219 chronic myeloid leukaemia patients with additional chromosomal abnormalities and/or tyrosine kinase domain mutations.

INTRODUCTION: To confirm the role of additional chromosomal abnormalities (ACAs) and kinase domain (KD) mutations in the progression and outcomes of Chronic myeloid leukaemia (CML) patients and the connection between them, we analysed the ACAs and KD mutations of 219 CML patients admitted to our hospital. METHODS: Cytogenetic analysis of metaphases was performed to detect ACAs, and the BCR-ABL1 KD was sequenced to detect KD mutations. RESULTS: Twenty-four patients (11.0%) had ACAs in addition to the BCR-ABL1 or t(9;22)(q34;q11) translocation. The most common abnormality was trisomy 8. Twelve different KD mutations were observed in 13 out of 53 imatinib-resistant patients (24.5%). p.(Y235H) (n = 3; 23.07%), p.(F359V) and p.(T315I) (n = 2; 15.38%) presented most frequently. KD mutations subtypes (p.(E255K), p.(T315I), p.(F359V), p.(M244V) and p.(L298V)) coexisted with ACAs. The incidence of CML progression was 12/22 (54.5%) in the group of patients with ACAs and/or KD mutations and 2/143 (1.4%) in the group of patients without ACAs or KD mutations (CI 95%, P < 0.001) and was higher in the KD mutations group than in the ACAs group (P = 0.046). The group of patients with ACAs and/or KD mutations had more men than the group of patients without ACAs or KD mutations (P = 0.013). CONCLUSION: We conclude that ACAs and/or KD mutations are related to CML progression and are adverse outcome factors. Their presence exhibits gender differences and is more common in males. p.(E255K), p.(T315I), p.(F359V), p.(M244V) and p.(L298V) emerge more frequently when ACAs and KD mutations coexist.