Beijing Dao Pei Hospital

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Our study includes 103 patients aged between 51 and 60 years who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) from matched sibling donors (MSDs) (n = 36), haploidentical donors (HIDs) (n = 56), and unrelated donors (URDs) (n = 11). Multivariate analysis exploring the relationship between risk factors and survival confirmed that survival outcomes were only independently impacted by Eastern Cooperative Oncology Group (ECOG) score (ECOG scores ≥2vs. ECOG scores of 0-1, overall survival [OS] HR: 2.91 [95% CI 1.35-6.27], p = 0.006; failure free survival [FFS] HR: 2.93 [95% CI 1.33-5.88], p = 0.006; graft-versus-host disease-free/relapse-free survival [GRFS] HR: 2.80 [95% CI 1.33-5.88], p = 0.006), while age, specific donor source and hematopoietic cell transplantation-comorbidity index (HCT-CI) score did not significantly influence prognosis in this age group. After applying propensity score-matching (PSM) to balance the pretransplant clinical factors between patients with ECOG scores 0-1 cohort and those with ECOG scores ≥2 cohort, poor performance status remains a negative factor for survival outcomes (OS p = 0.04; FFS p = 0.03; GRFS p = 0.03). Further analysis in subgroup patients with HCT-CI scores 0-1 found the retained significance of ECOG score in predicting inferior survival. In conclusion, our results indicate good long-term results of allo-HSCT in elderly SAA adults regardless of donor type. Higher ECOG score is associated with poor post-transplant outcomes and has to be taken into account for patients, even at a low-risk comorbidly burden.

Disturbances in transcriptional regulation during hematopoiesis can lead to aberrant hematopoietic differentiation and potential leukemogenesis. Given the high relapse risk of acute myeloid leukemia (AML), understanding its progression mechanisms and identifying prognostic biomarkers are crucial for improving treatment outcomes. Here, we applied a mitochondrial single-cell assay for transposase-accessible chromatin with sequencing mitochondria single-cell ATAC-seq (mtscATAC-seq), supplemented with single-cell RNA-seq, to comprehensively characterize AML cells. By constructing a single-cell hematopoiesis reference and mapping tumor cells to it, we identified significant alterations in chromatin accessibility of cis-regulatory elements (CREs) associated with AML differentiation. Using an in-house developed algorithm, cisGRN, we analyzed CRE dynamics and discovered that mutations in the zinc finger domain of WT1 are associated with decreased chromatin accessibility and hypermethylation at the regulatory regions of their target genes, leading to gene downregulation. Functional validation confirmed the pathogenic effects of five WT1 zinc finger mutations: R467Q, R467L, R467W, H470Y, and H470R. Additionally, we identified a CRE mutation that emerges early in hematopoiesis, introducing a new binding motif for CCAAT enhancer binding protein beta (CEBPB), which facilitates its binding to the enhancer, activating enhancer activity and GATA binding protein 4 (GATA4) expression, thereby promoting AML proliferation. These effects were validated through luciferase reporter assays and prime editing experiments. Using mitochondria DNA tracing and machine learning modeling, we identified relapse-associated clones resembling leukemia stem cells (LSCs) and uncovered marker genes in the clones that more accurately predict drug resistance and relapse risk. Collectively, our findings underscore the utility of combining mtscATAC-seq, lineage tracing, and gene regulatory network (GRN) analysis to uncover aberrant regulatory changes and track relapse-prone AML clones.

A second transplantation is almost the only salvage for patients encountering graft failure (GF) following first allogeneic stem cell transplantation. However, there were no standard protocols for second transplantations, and the role of changing donors remained controversial. We retrospectively studied 272 consecutive patients from 18 Chinese centers undergoing second transplantations due to GF, aiming to assess the impact of changing donors and the factors affecting second transplantation outcomes. The primary endpoint was neutrophil engraftment. Other endpoints included platelet engraftment, graft-versushost disease (GvHD), transplant-related mortality (TRM), relapse, and survival. Of the 272 patients, 193 (71.0%) patients experienced primary GF, and 70.6% (192) used a different second donor. Neutrophil engraftment was achieved in 218 (86.3%) patients by day (d)28, and platelet engraftment was achieved in 164 (70.0%) patients by d100. The 3-year cumulative incidence of acute GvHD, chronic GvHD, relapse, and TRM were 43.5%, 27.8%, 15.6%, and 44.6%, respectively. The 1-year and 3-year overall survival (OS) were 56.1% and 49.5%, respectively. Compared to using the same donor, changing donors significantly improved neutrophil engraftment (92.4% vs. 71.4%, P<0.001) and platelet engraftment (76.9% vs. 51.8%, P<0.001), 1-year TRM (34.8% vs. 56.3%, P<0.001), and OS (61.9% vs. 42.7%, P<0.001). Subgroup analysis confirmed engraftment benefit of changing donor in primary GF (P<0.001), but not in secondary GF (P=0.346). This is the largest multicenter study of second transplantations for GF, suggesting that changing donors might be critical for engraftment and survival after second transplantation.

Data sharing is not applicable to this article as no new data were created or analyzed in this study. Appendix S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

The authors declare no conflicts of interest. Data sharing is not applicable to this article as no new data were created or analyzed in this study.

This article describes a 6-year-old patient diagnosed with "systemic mastocytosis with AML1::ETO+ AML", he experience refractory disease during the course of treatment and salvage treatment was ineffective. The patient was administered gemtuzumab-ozogamicin therapy, resulting in rapid remission.