T-cell acute lymphoblastic leukemia (T-ALL) is one of the hematological malignancies. With the applications of chemotherapy regimens and allogeneic hematopoietic stem cell transplantation, the cure rate of T-ALL has been significantly improved. However, patients with relapsed and refractory T-ALL still lack effective treatment options. Gene mutations play an important role in T-ALL. The NOTCH1 gene mutation is the important one among these genetic mutations. Since the mutation of NOTCH1 gene is considered as a driving oncogene in T-ALL, targeting the NOTCH1 signaling patheway may be an effective option to overcome relapsed and refractory T-ALL. This review mainly summarizes the recent research advances of targeting on NOTCH1 signaling pathway in T-ALL.

Background Acute myeloid leukemia (AML) patients with normal karyotype (NK-AML) have significant variabilities in outcomes. The European Leukemia Net stratification system and some prognostic models have been used to evaluate risk stratification. However, these common standards still have some limitations. The biological functions and mechanisms of Small Integral Membrane Protein 3 (SMIM3) have seldomly been investigated. To this date, the prognostic value of SMIM3 in AML has not been reported. This study aimed to explore the clinical significance, biological effects and molecular mechanisms of SMIM3 in AML. Methods RT-qPCR was applied to detect the expression level of SMIM3 in bone marrow specimens from 236 newly diagnosed adult AML patients and 23 healthy volunteers. AML cell lines, Kasumi-1 and THP-1, were used for lentiviral transfection. CCK8 and colony formation assays were used to detect cell proliferation. Cell cycle and apoptosis were analyzed by flow cytometry. Western blot was performed to explore relevant signaling pathways. The biological functions of SMIM3 in vivo were validated by xenograft tumor mouse model. Survival rate was evaluated by Log-Rank test and Kaplan–Meier. Cox regression model was used to analyze multivariate analysis. The correlations between SMIM3 and drug resistance were also explored. Results Through multiple datasets and our clinical group, SMIM3 was shown to be significantly upregulated in adult AML compared to healthy subjects. SMIM3 overexpression conferred a worse prognosis and was identified as an independent prognostic factor in 95 adult NK-AML patients. Knockdown of SMIM3 inhibited cell proliferation and cell cycle progression, and induced cell apoptosis in AML cells. The reduced SMIM3 expression significantly suppressed tumor growth in the xenograft mouse model. Western blot analysis showed downregulation of p-PI3K and p-AKT in SMIM3-knockdown AML cell lines. SMIM3 may also be associated with some PI3K-AKT and first-line targeted drugs. Conclusions SMIM3 was highly expressed in adult AML, and such high-level expression of SMIM3 was associated with a poor prognosis in adult AML. Knockdown of SMIM3 inhibited the proliferation of AML through regulation of the PI3K-AKT signaling pathway. SMIM3 may serve as a potential prognostic marker and a therapeutic target for AML in the future.

Background: The epigenetic regulator additional sex combs-like 1 (ASXL1) is an adverse prognostic factor in acute myeloid leukemia (AML). However, the mutational spectrum and prognostic factors of ASXL1-mutated (ASXL1+) AML are largely unknown. We aim to evaluate the risk factors influencing the prognosis of ASXL1+ AML.Methods: We performed next-generation sequencing (NGS) in 1047 cases of de novo AML and discovered 91 ASXL1+ AML (8.7%). The Log-Rank test and Kaplan-Meier were used to evaluate survival rate, and the Cox regression model was used to analyze multivariate analysis. Results: In a total of 91 ASXL1+ AML, 86% had one or more co-mutations. The factors that had adverse impact on overall survival (OS) and event-free survival (EFS) are defined as high risk factors, including age ≥60 years, WBC count ≥50×109/L、FLT3-ITD mutations、RUNX1 mutations, and absence of AML1-ETO fusion gene. ASXL1 mutations without any risk factor were classified as single-hit ASXL1+ AML; ASXL1 mutations accompanied with one of the risk factors was referred to be double-hit ASXL1+ AML; ASXL1 mutations with two or more of the risk factors were designated triple-hit ASXL1+ AML. The combination of these risk factors had a negative influence on the prognosis of ASXL1+ AML. The median OS was not attained in single-hit ASXL1+ AML, 29.53 months in double-hit ASXL1+ AML, and 6.67 months in triple-hit ASXL1+ AML (P=0.003). The median EFS was not attained in single-hit ASXL1+ AML, 29.53 months in double-hit ASXL1+ AML, and 5.47 months in triple-hit ASXL1+ AML (P=0.002). Allogenic hematopoietic stem cell transplantation (allo-HSCT) improved the prognosis of double/triple-hit ASXL1+ AML patients.Conclusion: Our study provided new insights into the mutational spectrum and prognostic factors of ASXL1+ AML patients. Our primary data suggest that the risk factors in ASXL1+ AML contribute to the poor outcome of these patients. The management of ASXL1+ AML patients should be based on the risk factors and allo-HSCT is highly recommended for consolidation.