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Effects of Auer rod on prognosis in patients with freshly-diagnosed non-M3 type acute myeloid leukemia
Yarui HUANG, Xingqin HUANG, Xiangtao HUANG, Chengxin LUO, Shuangnian XU, Jieping CHEN
Journal of Army Medical University 2022, 44(3): 224-230
Published: 15 February 2022
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Objective

To investigate the effects of Auer rod on the prognosis of newly-diagnosed non-M3 type acute myeloid leukemia (AML).

Methods

A retrospective cohort study was performed on 154 patients initially diagnosed as non-M3 type AML in our center from January 2012 to December 2019. According to the presence or absence of Auer rod in the bone marrow blasts, the patients were divided into Auer rod positive and negative groups. Their follow-up data were obtained from medical records and through telephone conversations with the enrolled patients. Clinical data were compared between the 2 groups, including gender, age, white blood cell (WBC) count, platelet (PLT) count, hemoglobin (Hb), lactate dehydrogenase (LDH), French-American-British (FAB) classification, percentage of blast cells in bone marrow, and cytogenetic risk stratification. Kaplan-Meier survival analysis and multivariate COX regression model were used to analyze the difference in outcome of time-events between the 2 groups.

Results

As compared with the Auer rod negative group, the Auer rod positive group had higher proportion of M2 type (P<0.001) but lower proportion of M5 type (P=0.005) in FAB classification, lower percentage of bone marrow blasts (P<0.001), higher mutation frequency of WT1 gene (P=0.006), and lower mortality rate (P=0.008). The overall survival (OS) was significantly longer in the Auer rod positive group than the negative group (P=0.01). Multivariate COX regression analysis showed that Auer rod was an independent influencing factor for OS (HR=0.298, 95%CI: 0.104~0.853, P=0.024).

Conclusion

Auer rod is an independent prognostic factor of AML, and presents good prognostic value.

Open Access Full Length Article Issue
Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin
Zhe Chen, Qian Guo, Shichen Huang, Lei Li, Feng Wu, Zhilong Liu, Zhigang Li, Tao Chen, Guanbin Song, Shuangnian Xu, Jieping Chen, Yu Hou
Genes & Diseases 2024, 11(1): 397-412
Published: 25 January 2023
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Therapeutic targeting FOXO3A (a forkhead transcription factor) represents a promising strategy to suppress acute myeloid leukemia (AML). However, the effective inhibitors that target FOXO3A are lacking and the adaptive response signaling weakens the cytotoxic effect of FOXO3A depletion on AML cells. Here, we show that FOXO3A deficiency induces a compensatory response involved in the reactive activation of mTOR that leads to signaling rebound and adaptive resistance. Mitochondrial metabolism acts downstream of mTOR to provoke activation of JNK/c-JUN via reactive oxygen species (ROS). At the molecular level, FOXO3A directly binds to the promoter of G protein gamma subunit 7 (GNG7) and preserves its expression, while GNG7 interacts with mTOR and restricts phosphorylated activation of mTOR. Consequently, combinatorial inhibition of FOXO3A and mTOR show a synergistic cytotoxic effect on AML cells and prolongs survival in a mouse model of AML. Through a structure-based virtual screening, we report one potent small-molecule FOXO3A inhibitor (Gardenoside) that exhibits a strong effect of anti-FOXO3A DNA binding. Gardenoside synergizes with rapamycin to substantially reduce tumor burden and extend survival in AML patient-derived xenograft model. These results demonstrate that mTOR can mediate adaptive resistance to FOXO3A inhibition and validate a combinatorial approach for treating AML.

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