The 29th Annual Congress of the European Hematology Association (EHA) was held grandly in Madrid, Spain, from June 13 to 16, 2024. As the largest international conference in the field of hematology in Europe, it attracts experts and scholars from around the world each year to share and discuss innovative ideas and the latest scientific and clinical research findings in hematology. At this year's conference, Professor Jia Wei's team from Tongji Hospital, Huazhong University of Science and Technology had multiple studies selected for poster or e-poster presentations. This issue focuses on two studies in the field of myeloid tumors. One study (P487), conducted in collaboration with Associate Professor Yu Xiaoxuan from Nanjing University of Chinese Medicine, explores the relationship between UBE2Q1 and AML prognosis and its mechanism of affecting antigen presentation in AML. The other study (P1885) investigates the clinical prognosis and molecular characteristics of MDS patients with ASXL1 mutations.

UBE2Q1 Impairs Antigen Presentation in AML

Background The immune microenvironment of acute myeloid leukemia (AML) is in a suppressed state, primarily due to reduced antigen presentation function. Dendritic cells (DCs) play a crucial role in the immune response by capturing and processing antigens, then migrating to secondary lymphoid organs to present antigens to T cells, thereby mediating adaptive immunity. Inducing AML cells to differentiate into DCs helps address the issue of low immune reactivity in AML and plays a significant role in AML treatment. Ubiquitin-conjugating enzyme E2 Q1 (UBE2Q1) is associated with poor prognosis in hepatocellular carcinoma, breast tumors, colorectal cancer, and ovarian cancer. However, its role in AML remains unknown.

Objective This study aims to reveal the relationship between UBE2Q1 and AML prognosis, explore its novel mechanism in antigen presentation, and screen for safe and effective natural UBE2Q1 inhibitors.

Methods Bone marrow samples from AML patients diagnosed between July and October 2023 at the Hematology Department of Shanxi Bethune Hospital were analyzed using single-cell sequencing to evaluate the differential expression of UBE2Q1 in AML patients and healthy volunteers and its relationship with antigen presentation in AML. Kaplan-Meier analysis was used to assess the prognostic significance of UBE2Q1 in AML. Mass spectrometry (MS) identified potential interacting proteins of UBE2Q1. Flow cytometry determined the percentage change in DC maturation markers. High-throughput screening of 1896 traditional Chinese medicine monomers aimed to find safe and effective small molecule inhibitors of UBE2Q1.

Results Our study found that UBE2Q1 levels in AML patients were significantly higher than in healthy volunteers through single-cell transcriptome sequencing combined with clinical sample analysis. Survival analysis indicated that high UBE2Q1 expression was associated with poor survival in AML patients. Cell population analysis in AML patients showed that UBE2Q1 expression was related to antigen presentation in AML cells. Moreover, UBE2Q1 knockdown in AML cells increased the expression of the DC maturation marker CD86, an effect closely related to the ubiquitination of HDAC1. High-throughput screening of a compound library containing 1896 traditional Chinese medicine monomers identified gambogic acid as a compound targeting UBE2Q1 and regulating antigen presentation in AML cells. In vivo DC vaccine trials demonstrated that gambogic acid has a good anti-AML effect.

Conclusion This study reveals the relationship between UBE2Q1 and AML prognosis and its crucial role in antigen presentation in AML cells. It identifies the potential of UBE2Q1 as a therapeutic target in AML and screens gambogic acid as a potential UBE2Q1 inhibitor, providing new ideas for AML clinical treatment.

Clinical Prognosis and Molecular Characteristics of MDS Patients with ASXL1 Mutations

Background Myelodysplastic syndromes (MDS) are a group of myeloid tumors characterized by clonal proliferation of hematopoietic stem cells (HSCs), recurrent genetic abnormalities, ineffective hematopoiesis, peripheral blood cytopenias, and a high risk of progression to acute myeloid leukemia (AML). MDS is a highly heterogeneous hematologic disease, leading to significant differences in patient prognosis. Thus, there is an urgent need to identify reliable prognostic markers. ASXL1 mutations (ASXL1MUT) are prevalent in MDS patients, making this gene mutation a crucial focus of MDS research. While some studies suggest that ASXL1MUT is a poor prognostic factor in MDS patients, the exact mechanisms remain unclear. Current clinical prognostic scoring systems do not fully consider the impact of genetic mutations on prognosis.

Objective This study aims to explore the association between ASXL1MUT and clinical outcomes in MDS patients and to validate its impact as an independent risk factor on overall survival (OS) in high-risk MDS patients.

Methods In this dual-center prospective cohort study, comprehensive genomic sequencing was conducted on 210 MDS patients diagnosed between January 2017 and April 2023 at the Hematology Department of Shanxi Bethune Hospital and Tongji Hospital of Huazhong University of Science and Technology. Two main sequencing techniques were used to detect mutations associated with MDS: first-generation sequencing and next-generation sequencing. Except for two patients who underwent first-generation sequencing, all others were tested using next-generation sequencing.

Results ASXL1 mutations were observed in 44 MDS patients (20.95%), with 26 cases (59.09%) being frameshift mutations and 18 cases (40.91%) being non-frameshift mutations (Figures A and B). We found that ASXL1MUT co-occurred with RUNX1, U2AF1, TET2, EZH2, SRSF2, NRAS, and STAG2 mutations but was mutually exclusive with NPM1 mutations (Figure C). Importantly, compared to ASXL1 wild-type (ASXL1WT) patients, ASXL1MUT patients exhibited a higher tendency for progression to secondary acute myeloid leukemia (sAML) and a higher rate of disease progression. Additionally, among high-risk MDS patients (IPSS-R>3.5), those with non-frameshift ASXL1MUT had significantly shorter overall survival (OS) compared to those with frameshift ASXL1MUT (Figure D). Multivariate analysis also indicated that non-frameshift ASXL1MUT was an independent risk factor for OS in high-risk MDS patients, highlighting the clinical significance of ASXL1MUT in the MDS context. Furthermore, to explore the impact of ASXL1MUT variant allele frequency (VAF) on MDS prognosis, we divided ASXL1MUT MDS patients into high VAF and low VAF groups using a median value of 37.25% as the cut-off. There was no statistically significant difference in OS and PFS between the two groups.

Conclusion In summary, ASXL1MUT increases the risk of AML development and shows higher disease progression rates in MDS patients. Non-frameshift ASXL1MUT, in particular, is an independent risk factor for poor overall survival in high-risk MDS patients classified by IPSS-R.