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.

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and poorly understood hematopoietic malignancy. This study aimed to investigate the clinical characteristics and prognostic factors in patients with primary BPDCN. Methods: Patients diagnosed with primary BPDCN from 2000 to 2019 were extracted from the Surveillance, Epidemiology and End Results (SEER) database. Independent prognostic factors were evaluated based on the univariate and multivariate Cox regression analysis. The nomogram was then constructed to predict the overall survival of primary BPDCN patients at 3, 5 and 10 years after diagnosis. Results: A total of 668 primary BPDCN patients were included in this study. The average age was 35.7 ± 25.4 years, with 68.7% being male. The mostly affected sites were lymph nodes (59.9%). Most patients (69.9%) received chemotherapy or radiation therapy. For all the patients, the 1-year, 3-year, 5-year, and 10-year overall survival (OS) were 78.0%, 62.6%, 59.0%, and 56.3%, respectively, and the corresponding disease-specific survival (DSS) were 80.6%, 66.8%, 63.5, and 61.8%, respectively. Multivariate cox analysis indicated that age and marital status of other (divorced, widowed and separated) at diagnosis were independent prognostic factors for DSS, but only age was for OS. The 5-year OS rate significantly declined with increasing age: age <15, 89.3%; age 15-39, 57.9%; age 40-64, 51.2%; age ≥65, 26.1%. Nomograms were further constructed to predict the possibility of OS and DSS with good performances. Conclusions: Primary BPDCN is a rare disease, age and marital status were associated with survival of primary BPDCN patients, and age was an independent prognostic factor for OS.

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: The genomic data and clinical information were retrieved from TCGA and GEO, respectively. The gene mutation data of AML were obtained from cBioPortal. 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. Weighted gene co-expression network analysis (WGCNA) was performed to identify co-expression modules and screen the hub genes. 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. Patients with C1 subtype showed higher expression level of the five candidate genes and worse prognosis compared with C2 subtype. Moreover, 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. Finally, WCGNA identified a module and five hub genes that can be used for predicting the response of AML patients to mRNA vaccine. 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.

Background: HHV8-positive diffuse large B-cell lymphoma, not otherwise specified (HDN) is a rare and aggressive lymphoma that usually arises in association with HHV8-positive multicentric Castleman disease. The epidemiology, treatment patterns and survival outcomes of HDN are poorly understood. Methods: A retrospective analysis was performed for 67 patients with HDN diagnosed from 2011 to 2020 using the SEER database. The clinicopathologic characteristics, treatment modalities and survival outcomes of HDN patients were evaluated. Kaplan-Meier analysis and Cox regression analysis were employed to identify prognostic factors for overall survival (OS) and disease-specific survival (DSS). Results: The median age at diagnosis was 51.8 years, and 79.1% of patients were male. The primary site distribution was mainly nodal (79.1%), while the extranodal sites were rarely involved (20.9%). The majority of patients were white (65.7%). Only 3.0% of patients received radiotherapy, while 55.2% received chemotherapy. The 1-year, 3-year and 5-year OS was 67.4%, 65.6%, 58.4%, and 56.3%, respectively, and the corresponding DSS was 73.1%, 73.1%, and 67.8%, respectively. The diagnosis year group of 2016-2020 had a significantly worse OS than the diagnosis year group of 2011-2015 (P = 0.040), but not for DSS (P = 0.074). No significant survival improvement was observed in patients underwent chemotherapy. Age and marital status were independent prognostic factors for OS, and age was an independent prognostic factor for DSS. Conclusions: HDN is a rare and aggressive disease, our study provides a comprehensive overview of the epidemiology, treatment patterns and survival outcomes of HDN patients for the first time. We revealed that older age and marital status of single were associated with worse survival of HDN, while chemotherapy was not associated with improved survival outcomes in HDN patients.

Although treatment of B cell precursor acute lymphoblastic leukemia (BCP-ALL) in children has shown eminent progress over the past decades, about 15% of patients can still not be cured, however. Therefore, new therapeutic strategies are warranted. FOXO1 together with other transcription factors including EBF1, PAX5 and TCF3 plays a central role in differentiation of pre-B-cells. In cooperation with PAX5 and other B-cell transcription factors, FOXO1 induces expression of SYK, BLNK, RAG1, RAG2, AICDA and IL7RA genes. Of note, SYK and IL7RA signaling contribute to the oncogenic program of BCP-ALL, which utilize pre-B cell survival and proliferation program. In this study, we demonstrate that FOXO1 is highly expressed in most of the BCP-ALL cell lines. By using immunofluorescence assays we show that FOXO1 is localized in the nucleus of BCP-ALL cells. Overexpression of constitutively active AKT1 (inactivating FOXO1) negatively regulates the growth of BCP-ALL cells. Inhibition of FOXO1 by shRNA results in cell death in the RS4;11 BCP-ALL cell line. BCP-ALL cells are more sensitive to growth arrest and apoptosis induced by a small molecular FOXO1 inhibitor AS1842856 than other classical Hodgkin lymphoma and non-Hodgkin lymphoma cell lines. Gene expression profiling of BCP-ALL cells after treatment with the FOXO1 inhibitor for 24h shows the significantly down-regulation of FOXO target genes including VPREB3, IL1B, KLHL24 and BNIP3L. Interestingly, at the same time, some FOXO targets like NOXA, RUNX2 and PRDM1 were found upregulated, indicating a complex effect of the FOXO1 inhibitor. We conclude that FOXO1 expression is critical for the BCP-ALL oncogenic program and its targeting represents a novel therapeutic approach. Citation Format: Fan Wang, Alexey Ushmorov, Thomas Wirth. Role of FOXO1 in oncogenic program of B cell precursor acute lymphoblastic leukemia (BCP-ALL). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2009.

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