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Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In this study, a total of 1,474 newly diagnosed AML patients with RNA sequencing data were enrolled, and targeted or whole exome sequencing data were obtained in 94% cases. The correlation of aging-related factors including age and clonal hematopoiesis (CH), gender, and genomic/transcriptomic profiles (gene fusions, genetic mutations, and gene expression networks or pathways) was systematically analyzed. Overall, AML patients aged 60 y and older showed an apparently dismal prognosis. Alongside age, the frequency of gene fusions defined in the World Health Organization classification decreased, while the positive rate of gene mutations, especially CH-related ones, increased. Additionally, the number of genetic mutations was higher in gene fusion--negative (GF-) patients than those with GF. Based on the status of CH- and myelodysplastic syndromes (MDS)-related mutations, three mutant subgroups were identified among the GF-AML cohort, namely, CH-AML, CH-MDS-AML, and other GF-AML. Notably, CH-MDS-AML demonstrated a predominance of elderly and male cases, cytopenia, and significantly adverse clinical outcomes. Besides, gene expression networks including HOXA/B, platelet factors, and inflammatory responses were most striking features associated with aging and poor prognosis in AML. Our work has thus unraveled the intricate regulatory circuitry of interactions among different age, gender, and molecular groups of AML. [ABSTRACT FROM AUTHOR]

Optimal post-remission treatment for individual favorable and intermediate risk acute myeloid leukemia (AML) patients has not yet been established. Human leukocyte antigen (HLA)-mismatched stem cell microtransplantation (MST), may improve outcomes and avoid graft-versus-host disease in patients with first complete remission of AML. We retrospectively analyzed the efficacy, safety, and survival of 63 patients with favorable- or intermediate-risk AML who received MST, autologous stem cell transplantation (ASCT), or cytarabine single agent (CSA) as post-remission treatment from January 2014 to August 2021. The neutrophil recovery time was shorter in the MST group than in the CSA group. The 2-year cumulative incidences of relapse in the MST, ASCT, and CSA groups were 27.27%, 29.41%, and 41.67%, respectively. During follow-up, 21 patients (33.30%) died of relapse, including six (9.52%), five (7.94%), and 10 (15.84%) in the MST, ASCT, and CSA groups, respectively. The estimated 2-year overall survival (OS) and relapse-free survival (RFS) were 62.20% vs. 50.00% (P = 0.101) and 57.10% vs. 50.00% (P = 0.136), in the >60 years MST and CSA groups (P = 0.101). The estimated 2-year OS was 100%, 66.20%, and 69.10% in the MST, ASCT, and CSA groups (MST vs CSA, P = 0.044), meanwhile, the estimated 2-year RFS was 100%, 65.40%, and 59.80% in patients ≤60 years. MST, ASCT, and CSA are acceptable post-remission treatments for patients with favorable- and intermediate-risk AML and may not only improve the prognosis of the elderly but also prolong the OS and RFS of favorable- or intermediate-risk patients ≤60 years. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the incidence and prognostic significance of common cytogenetic and molecular abnormalities in patients with TP53-mutated and non-TP53-mutated acute myeloid leukemia (AML). We retrospectively analyzed the clinical data of 326 patients with newly diagnosed AML hospitalized in our institution between October 2015 and June 2021. Classification variables were reported as percentages and compared by χ2 tests. Survival rates were evaluated by the Kaplan-Meier method. The incidence of TP53 mutations in AML patients in this clinic was 9.8%, of whom 87.5% patients were over 50 years old. The common concurrent mutations of TP53 were DNMT3A, IDH2, NRAS and TET2. Patients with a TP53 variant allele frequency (VAF) ≤ 40% had better overall survival (OS) than patients with a VAF >40%. Compared with non-TP53-mutated patients, significantly more TP53-mutated patients were gene-fusion negative, +mar, – 7/del (7q), – 5/del (5q), – 17/17p-, – 12/12p-, incomplete (inc) karyotype, or complex karyotype (CK), and had FLT3-ITD or IDH2 mutations, as well as a lower complete remission (CR) rate (31.3%) and higher recurrence rate (80.0%). The 2-year OS rates of TP53-mutated and non-TP53-mutated patients were 18.8% and 47.3%, respectively (P < 0.001). Univariate analysis showed that non-TP53-mutated patients with MLL family gene fusion, +mar or – 17/17p – karyotype, and FLT3-ITD mutations had a poor prognosis, while t(8; 21) karyotype was associated with a better prognosis. TP53-mutated patients with – 7/del (7q) or – 5/del (5q) karyotype had a poor prognosis. The cytogenetic and molecular landscapes differed between TP53-mutated and non-TP53-mutated patients, and some abnormalities had different values between them. [ABSTRACT FROM AUTHOR]

To explore the clinical outcomes and characteristics of TP53-mutated primary myelodysplastic syndromes (MDS). A total of 74 de novo primary MDS patients who were diagnosed and treated in the Department of Hematology of our hospital from January 2018 and September 2021 were analyzed retrospectively. All patients had evaluable blood cell counts, mean corpuscular volume (MCV), lactate dehydrogenase (LDH), bone marrow (BM) morphology, biopsy, and MDS-related 20-gene mutations sequencing. In addition, 69 of 74 patients had complete cytogenetic analysis through conventional chromosome analysis and fluorescence in-situ hybridization. Patients were divided into two cohorts, the TP53-mutated type (TP53Mut) group (n = 19) and TP53 wild type (TP53WT) group (n = 55). Compared with the TP53WT group, patients in the TP53Mut group had higher ratios of cytogenetic abnormalities (82.4% vs. 30.8%, P < 0.001), with 5q- karyotype (64.70% vs. 38.5%, P < 0.001), complex karyotype(CK) (64.70% vs. 38.5%, P < 0.001), HR-MDS (94.7% vs. 61.8%, P = 0.008), and acute myelogenous leukemia (AML) transformation (26.3% vs. 12.7%, P < 0.001). Interestingly, patients in the TP53Mut group had lower median MCV than the TP53WT group (94.40 fl vs. 101.90 fl, P = 0.008). Furthermore, MCV = 100 fl as cutoff, and found that MCV ≤ 100 fl was more common in the TP53Mut group (73.7% vs. 38.2%, P < 0.001). After 1–4 courses of HMA ± chemotherapy, the overall response rate of the TP53Mut group was higher than the TP53WT group (83.3% vs. 71.4%, P = 0.012). With the median follow-up 12.0 months (1–46 months), the results show that the median OS and leukemia-free survival (LFS) of TP53Mut group was significantly shorter than the TP53WT group (P = 0.0018; P = 0.0310). Results of multivariate Cox proportional hazard analyses show TP53 mutation was an independent prognostic factor for the OS (HR 2.724, 95%CI 1.099–6.750, P = 0.030). TP53-mutated primary MDS patients were associated with higher frequency of cytogenetic abnormalities, with 5q- karyotype, CK, AML transformation, higher risk IPSS-R, lower MCV and sensitive to HMA treatment, but worse survival. [ABSTRACT FROM AUTHOR]

Nucleophosmin 1 (NPM1, also known as B23) is a multifunctional protein involved in a variety of cellular processes, including ribosomal maturation, centrosome replication, maintenance of genomic stability, cell cycle control, and apoptosis. NPM1 is the most commonly mutated gene in adult acute myeloid leukemia (AML) and is present in approximately 40% of all AML cases. The underlying mechanisms of mutant NPM1 (NPM1mut) in leukemogenesis remain unclear. This review summarizes the structure and physiological function of NPM1, mechanisms underlying the pathogenesis of NPM1-mutated AML, and the potential role of NPM1 as a therapeutic target. It is reported that dysfunctional NPM1 might cause AML pathogenesis via its role as a protein chaperone, inhibiting differentiation of leukemia stem cells and regulation of non-coding RNAs. Besides conventional chemotherapies, NPM1 is a promising therapeutic target against AML that warrants further investigation. NPM1-based therapeutic strategies include inducing nucleolar relocalisation of NPM1 mutants, interfering with NPM1 oligomerization, and NPM1 as an immune response target. [ABSTRACT FROM AUTHOR]

Acute myeloid leukaemia (AML) is a haematopoietic malignancy with a dismal outcome. Consequently, risk stratification based on more effective prognostic biomarkers is crucial to make accurate therapy decisions. T cell receptor gamma alternative reading frame protein (TARP) has been reported in prostate and breast cancers, but its correlation with AML remains unclear. Differential expression of TARP mRNA in different AML subtypes was analysed using the UALCAN online platform. Its relationship with baseline clinical attributes, survival and efficacy were analysed based on three GSE1159, GSE425 and GSE6891 microarray datasets downloaded from Gene Expression Omnibus (GEO) and Oncomine databases. Quantitative real-time PCR was performed to determine mRNA levels of TARP in bone marrow mononuclear cells (BMMCs) isolated from AML patients. TARP was significantly overexpressed in AML patients. In AML, relatively low TARP expression was associated with the CBFβ-MYH11 fusion gene. The proportion of FLT3 mutations was significantly higher in non-adolescent and young adult (non-AYA, >39 years of age) AML patients who had high TARP levels but not in AYA (15–39 years) patients. High expression of TARP was related to poor outcome by univariate analysis but not by multivariate analysis and unsatisfactory therapeutic effects, which could be overcome by haematopoietic stem cell transplantation (HSCT). Our findings suggest that TARP might be a potential prognostic marker of AML and serve as a promising immunotherapeutic target. [ABSTRACT FROM AUTHOR]