[Prognostic Value of IGF2BP3 Gene Expression Levels in Patients with Acute Myeloid Leukemia].

OBJECTIVE: To investigate the relationship between IGF2BP3 gene expression and prognosis in patients with acute myeloid leukemia (AML). METHODS: High throughput transcriptome sequencing was performed on bone marrow primary leukemia cells from 27 patients with AML in our center, the relationship between IGF2BP3 expression levels and clinical characteristics were analyzed and verify the samples from patients with newly treated AML and refractory AML. The expression level of IGF2BP3 gene were analyzed in 20 healthy subjects and 26 patients with AML. The expression of IGF2BP3 in two anthracycline-resistant cell lines (HL60/ADR, K562/ADR) was detected by RT-qPCR and Western blot, and the expression difference of IGF2BP3 was compared with that in sensitive cells (HL60, K562). The relationship between the expression level of IGF2BP3 in patients with AML and prognostic were analyzed through data analysis of 746 patients with AML, and the prognostic value of IGF2BP3 in AML was analyzed by multivariate Cox regression analysis. RESULTS: In the bone marrow primary leukemia cells of 27 AML patients in our center, the expression level of IGF2BP3 in patients with refractory AML was significantly higher than that in chemotherapy sensitive patients (P =0.0343). The expression of IGF2BP3 in leukemia patients with extramedullary infiltration (EMI) was significantly higher than that in AML patients without extramedullary infiltration (P =0.0049). Compared with healthy subjects (n=20), IGF2BP3 expression in AML patients (n=26) was higher (P =0.0009). The expression of IGF2BP3 mRNA in the anthracycline resistant cell lines (HL60/ADR, K562/ADR) was significantly higher than that in the sensitive cell lines (K562/ADR vs K562,P =0.0430; HL60/ADR vs HL60, P =0.7369). Western blot results showed that the expression of IGF2BP3 protein in mycin resistant cells was significantly higher than that in sensitive cells (P < 0.001). qPCR results showed that the expression level of IGF2BP3 mRNA in refractory AML patients was significantly higher than that in patients with chemotherapy sensitive (P =0.002). High expression of IGF2BP3 was associated with poor prognosis in AML (P < 0.05) in 3 large sample cohorts of AML patients. Univariate and multivariate prognostic analyses demonstrated that high expression of IGF2BP3 was significantly associated with shorter event-free survival (EFS, HR=1.887, P =0.024) and overall survival (OS, HR=1.619, P =0.016). CONCLUSION: The high expression of IGF2BP3 gene may be an important factor in the poor prognosis of AML, suggesting that IGF2BP3 gene may be a new molecular marker for the clinical prognosis evaluation and treatment strategy of AML.

[Venetoclax Combined with CACAG Regimen in the Treatment of Patients with Refractory/Relapse Acute Myeloid Leukemia: A Prospective Clinical Study].

OBJECTIVE: To investigate the efficacy and safety of Venetoclax combined with CACAG regimen in treatment of patients with refractory/relapse acute myeloid leukemia(R/R AML). METHODS: The study was a singlecenter prospective clinical trial. The enrolled patients met the criteria for R/R AML. Treatment included Azacidine(75 mg/m2，d 1-7), Ara-C (75-100 mg/m2, q12h, d 1-5), Aclacinomycin(20 mg d1,d3,d5), Chidamide(30 mg d1,d4), Venetoclax(100 mg d1, 200 mg d2, 400 mg d3-d14, in combination with Triazole Drug, reduced to 100 mg/d), and granulocyte colony-stimulating factor (300 µg /d until neutrophil recovery). The primary endpoint of observation was overall response rate after 1 course of treatment. RESULTS: A total of 19 patients were enrolled from January 2022 to April 2023. After 1 course of treatmen, the overall response rate was 81.3%(13/16), the CR rate was 68.8%(11/16), and the PR was 12.5%(2/16). Among the 11 patients who got CR/CRi, 8 cases achieved CRm (minimal residual disease negative CR) and 3 cases did not. As of March 27, 2023, the median follow-up time was 111(19-406) days. The six-month overall survival and progression-free survival rates were both 55.7%, the 1-year overall survival and progression-free survival rates were 46.4% and 47.7%, respectively. In addition, compared with the non-CRm group, CRm patients had a better PFS (377 days vs 111 days, P =0.046). Treatment-related adverse events were mainly 3-4 degrees of bone marrow suppression, complicated by various degrees of infection(n=12), hypokalemia(n=12) and hypocalcemia (n=10) and elevated liver enzymes (n=8), of which 3/4 degrees accounted for 47.4%(9/19). CONCLUSION: The Venetoclax combined with CACAG regimen is an effective salvage therapy for patients with R/R AML, with high remission rate and safety profile.

A novel scoring system for the quantitative prediction of prognosis in acute myeloid leukemia.

Background: Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy. Patient prognosis cannot be accurately assessed in National Comprehensive Cancer Network (NCCN) risk stratification subgroups based on the current criteria. This study aimed to develop a novel prognostic score model for the quantitative prediction of prognosis in AML. Results: We developed a prognostic risk scoring model of AML using differentially expressed genes to predict prognosis in patients with AML. Furthermore, we evaluated the effectiveness and clinical significance of this prognostic model in 4 AML cohorts and 905 patients with AML. A prognostic risk scoring model of AML containing eight prognosis-related genes was constructed using a multivariate Cox regression model. The model had a higher predictive value for the prognosis of AML in the training and validation sets. In addition, patients with lower scores had significantly better overall survival (OS) and even-free survival (EFS) than those with higher scores among patients with intermediate-risk AML according to the NCCN guidelines, indicating that the model could be used to further predict the prognosis of the intermediate-risk AML populations. Similarly, patients with high scores had remarkably poor OS and EFS in the normal-karyotype populations, indicating that the scoring model had an excellent predictive performance for patients with AML having normal karyotype. Conclusions: Our study provided an individualized prognostic risk score model that could predict the prognosis of patients with AML.

Emergence of an ancient and pathogenic mammarenavirus.

Emerging zoonoses of wildlife origin caused by previously unknown agents are one of the most important challenges for human health. The Qinghai-Tibet Plateau represents a unique ecological niche with diverse wildlife that harbours several human pathogens and numerous previously uncharacterized pathogens. In this study, we identified and characterized a novel arenavirus (namely, plateau pika virus, PPV) from plateau pikas (Ochotona curzoniae) on the Qinghai-Tibet Plateau by virome analysis. Isolated PPV strains could replicate in several mammalian cells. We further investigated PPV pathogenesis using animal models. PPV administered via an intraventricular route caused trembling and sudden death in IFNαßR-/- mice, and pathological inflammatory lesions in brain tissue were observed. According to a retrospective serological survey in the geographical region where PPV was isolated, PPV-specific IgG antibodies were detected in 8 (2.4%) of 335 outpatients with available sera. Phylogenetic analyses revealed that this virus was clearly separated from previously reported New and Old World mammarenaviruses. Under the co-speciation framework, the estimated divergence time of PPV was 77-88 million years ago (MYA), earlier than that of OW and NW mammarenaviruses (26-34 MYA).