The FOXO1 transcription factor plays an essential role in the regulation of proliferation and survival programs at early stages of B-cell differentiation. Here, we show that tightly regulated FOXO1 activity is essential for maintenance of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Genetic and pharmacological inactivation of FOXO1 in BCP-ALL cell lines produced a strong antileukemic effect associated with CCND3 downregulation. Moreover, we demonstrated that CCND3 expression is critical for BCP-ALL survival and that overexpression of CCND3 protected BCP-ALL cell lines from growth arrest and apoptosis induced by FOXO1 inactivation. Most importantly, pharmacological inhibition of FOXO1 showed antileukemia activity on several primary, patient-derived, pediatric ALL xenografts with effective leukemia reduction in the hematopoietic, lymphoid, and central nervous system organ compartments, ultimately leading to prolonged survival without leukemia reoccurrence in a preclinical in vivo model of BCP-ALL. These results suggest that repression of FOXO1 might be a feasible approach for the treatment of BCP-ALL.

BACKGROUND Hodgkin lymphoma survivors demonstrated increased risk of secondary primary malignancies (SPMs), but comprehensive analysis of the risk and outcome of SPMs in classical Hodgkin lymphoma (cHL) patients has not yet been reported. METHODS Patients with classical Hodgkin Lymphoma from 1975 to 2017 were identified from the Surveillance, Epidemiology and End Results (SEER) database. Standardized incidence ratios (SIRs) were calculated for the risk of solid and hematologic SPMs in cHL patients compared to the general population. The outcome of cHL patients developing SPMs were assessed by performing survival, competing risks regression and cox proportional regression analyses. RESULTS In a follow-up of 26,493 cHL survivors for 365,156 person years, 3,866 (14.59%) secondary cancers were identified, with an SIR of 2.09 (95% CI: 2.02 - 2.15). The increased risk was still notable after follow-up of 10 years or more, and the risk is more pronounced for patients with female gender, younger age, advanced stage, chemotherapy and radiation therapy. The overall survival is worse for cHL patients with SPMs after 5 years of follow-up (P < 0.0001). The main cause of death for cHL patients with SPMs is not cHL but other causes including SPMs. Multivariate Cox regression analysis confirmed SPMs as an independently adverse prognostic factor for cHL survivors (hazard ratio, 1.08; 95% CI, 1.03-1.14, P = 0.002). CONCLUSIONS There is a significantly increased risk of developing SPMs for cHL survivors. The overall survival is worse for cHL patients and SPMs is an independent prognostic factor for cHL.

Background Acute myeloid leukemia (AML) is a highly aggressive hematological malignancy, and there has not been any significant improvement in therapy of AML over the past several decades. The mRNA vaccines have become a promising strategy against multiple cancers, however, its application on AML remains undefined. In this study, we aimed to identify novel antigens for developing mRNA vaccines against AML and explore the immune landscape of AML to select appropriate patients for vaccination. Methods Genomic data and gene mutation data were retrieved from TCGA, GEO and cBioPortal, respectively. GEPIA2 was used to analyze differentially expressed genes. The single cell RNA-seq database Tumor Immune Single-cell Hub (TISCH) was used to explore the association between the potential tumor antigens and the infiltrating immune cells in the bone marrow. Consensus clustering analysis was applied to identify distinct immune subtypes. The correlation between the abundance of antigen presenting cells and the expression level of antigens was evaluated using Spearman correlation analysis. The characteristics of the tumor immune microenvironment in each subtype were investigated based on single-sample gene set enrichment analysis. Results Five potential tumor antigens were identified for mRNA vaccine from the pool of overexpressed and mutated genes, including CDH23, LRP1, MEFV, MYOF and SLC9A9, which were associated with infiltration of antigen-presenting immune cells (APCs). AML patients were stratified into two immune subtypes Cluster1 (C1) and Cluster2 (C2), which were characterized by distinct molecular and clinical features. C1 subtype demonstrated an immune-hot and immunosuppressive phenotype, while the C1 subtype had an immune-cold phenotype. Furthermore, the two immune subtype showed remarkably different expression of immune checkpoints, immunogenic cell death modulators and human leukocyte antigens. Conclusion CDH23, LRP1, MEFV, MYOF and SLC9A9 were potential antigens for developing AML mRNA vaccine, and AML patients in immune subtype 1 were suitable for vaccination. Supplementary Information The online version contains supplementary material available at 10.1007/s12094-023-03108-6.