Clinical and biological implications of mutational spectrum in acute myeloid leukemia of FAB subtypes M4 and M5

Cheng, Zhiheng; Hu, Kai; Tian, Li; Dai, Yifeng; Pang, Yifan; Cui, Wei; Zhao, Haixia; Qin, Tong; Han, Yu; Hu, Ning; Chen, Li; Wang, Chao; Zhang, Yijie; Wu, Depei; Ke, Xiaoyan; Shi, Jianxin; Fu, Lin

doi:10.1038/s41417-018-0013-6

Cited by 11 publications

(17 citation statements)

References 33 publications

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“…Multivariate analysis of the chemotherapy‐only group was consistent with previous studies in that older age (≥60 years), more BM blasts (≥70%), mutations in TP53 and DNMT3A also independently contributed to shorter EFS and OS . The effect of high DDIT4 expression on survival was not reproduced in the allo‐HSCT group, whereas WBC count ≥ 15 × 10 9 /L, FLT3‐ITD and TP53 mutation were associated with poor OS or EFS, suggesting that allo‐HSCT could ameliorate the adverse prognostic effect of high DDIT4 expression in AML.…”

Section: Discussionsupporting

confidence: 83%

“…Multivariate analysis of the chemotherapy-only group was consistent with previous studies in that older age (≥60 years), more BM blasts (≥70%), mutations in TP53 and DNMT3A also independently contributed to shorter EFS and OS. [25][26][27][28] To summarize, our results indicated that enhanced DDIT4 expression could be a poor prognostic factor for AML patients treated with chemotherapy alone, and these patients might benefit from allo-HSCT. We were able to identify a unique gene expression pattern and cell signalling pathways associated with DDIT4 expression, which could shed lights on the role of DDIT4 in leukaemogenesis.…”

Section: Chemotherapy-only Groupmentioning

confidence: 63%

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Up‐regulation of DDIT4 predicts poor prognosis in acute myeloid leukaemia

Cheng

Dai

Pang

et al. 2019

J Cellular Molecular Medi

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The mammalian target of rapamycin (mTOR) inhibitor, DNA damage inducible transcript 4 (DDIT4), has inducible expression in response to various cellular stresses. In multiple malignancies, studies have shown that DDIT4 participates in tumorigenesis and impacts patient survival. We aimed to study the prognostic value of DDIT4 in acute myeloid leukaemia (AML), which is currently unclear. Firstly, The Cancer Genome Atlas was screened for AML patients with complete clinical characteristics and DDIT4 expression data. A total of 155 patients were included and stratified according to the treatment modality and the median DDIT4 expression levels. High DDIT4 expressers had shorter overall survival (OS) and event‐free survival (EFS) than the low expressers among the chemotherapy‐only group (all P < .001); EFS and OS were similar in the high and low DDIT4 expressers of the allogeneic haematopoietic stem cell transplantation (allo‐HSCT) group. Furthermore, in the DDIT4high group, patients treated with allo‐HSCT had longer EFS and OS than those who received chemotherapy alone (all P < .01). In the DDIT4low group, OS and EFS were similar in different treatment groups. Secondly, we analysed two other cytogenetically normal AML (CN‐AML) cohorts derived from the Gene Expression Omnibus database, which confirmed that high DDIT4 expression was associated with poorer survival. Gene Ontology (GO) enrichment analysis showed that the genes related to DDIT4 expression were mainly concentrated in the acute and chronic myeloid leukaemia signalling pathways. Collectively, our study indicates that high DDIT4 expression may serve as a poor prognostic factor for AML, but its prognostic effects could be outweighed by allo‐HSCT.

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Section: Discussionsupporting

confidence: 83%

Section: Chemotherapy-only Groupmentioning

confidence: 63%

Up‐regulation of DDIT4 predicts poor prognosis in acute myeloid leukaemia

Cheng

Dai

Pang

et al. 2019

J Cellular Molecular Medi

Self Cite

View full text Add to dashboard Cite

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“…Multivariate analysis indicated that in the chemotherapy-only group, age ≥60 years, BM blasts ≥70%, and WBC count ≥15 × 10 9 /L also independently contribute to poor survival. This is concordant with older studies that older age confers unfavorable prognosis in AML, possibly due to higher mutation burden, lower baseline performance status and more co-morbidities in this population (23). The deleterious effects of highly-active bone marrow blast proliferation and high peripheral WBC count on AML remission rate and survival are also well described in previous findings that they have adverse effect on OS (24,25).…”

Section: Discussionsupporting

confidence: 90%

Upregulation of Glutamic-Oxaloacetic Transaminase 1 Predicts Poor Prognosis in Acute Myeloid Leukemia

et al. 2020

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One of the key features of acute myeloid leukemia (AML), a group of very aggressive myeloid malignancies, is their strikingly heterogenous outcomes. Accurate biomarkers are needed to improve prognostic assessment. Glutamate oxaloacetate transaminase 1 (GOT1) is essential for cell proliferation and apoptosis by regulating cell's metabolic dependency on glucose. It is unclear whether the expression level of GOT1 has clinical implications in AML. Therefore, we analyzed the data of 155 AML patients with GOT1 expression information from The Cancer Genome Atlas (TCGA) database. Among them, 84 patients were treated with chemotherapy alone, while 71 received allogeneic hematopoietic stem cell transplantation (allo-HSCT). In both treatment groups, high GOT1 expression was associated with shorter event-free survival (EFS) and overall survival (OS) (all P < 0.05). Multivariate analysis identified several independent risk factors for both EFS and OS in the chemotherapy-only group, including high GOT1 expression, age ≥60 years, white blood cell count ≥15 × 10 9 /L, bone marrow blasts ≥70%, and DNMT3A, RUNX1 or TP53 mutations (all P < 0.05); but in the allo-HSCT group, the only independent risk factor for survival was high GOT1 expression (P < 0.05 for both EFS and OS). Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the genes related to GOT1 expression were mainly concentrated in "hematopoietic cell lineage" and "leukocyte transendothelial migration" signaling pathways. Collectively, GOT1 expression may be a useful prognostic indicator in AML, especially in patients who have undergone allo-HSCT.

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“…Some of the studies suggested that higher IDO expression is observed in the FAB-M5 subtype (19,30,31). The FAB-M5 subtype is associated with leukemia derived from a myelomonocytic lineage (38), and as aforementioned, IDO expression on mononuclear cells, including monocytes and monocyte-derived DCs has been found. As FAB-M5 is leukemia of monocytic origin and IDO can be expressed by these cells, it could account for this correlation.…”

Section: Discussionmentioning

confidence: 92%

Investigating the Role of Indoleamine 2,3-Dioxygenase in Acute Myeloid Leukemia: A Systematic Review

2021

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Background: The immunomodulatory enzyme, indoleamine 2,3-dioxygenase (IDO) facilitates tryptophan catabolism at the rate-limiting step of the kynurenine (Kyn) pathway. IDO expression and elevations in Kyn metabolites are associated with immunosuppressive tumor microenvironment including T cell proliferative arrest and generation of regulatory T cells (Tregs) which can favor tumor progression. However, the extent of the role of IDO in acute myeloid leukemia (AML) is currently ill-defined. This study reviews the role of IDO-driven Treg function in AML and evaluates the current body of evidence implicating IDO in AML pathogenesis.Method: Studies related to IDO in AML were identified through a systematic review of PubMed and Scopus. Data extracted described sample analysis, IDO expression, IDO in prognosis, techniques used in Treg phenotypic studies, and the effect of IDO inhibitors.Results: Twenty studies were included in the systematic review. Expression of IDO was identified in a range of cells in AML, both inducible and constitutive. Seven studies indicated an association between elevated expression and poor clinical prognosis. Six studies suggested a positive correlation between IDO expression and Treg induction, with FoxP3 being the prominent Treg phenotypic marker. Of eight studies investigating IDO inhibition, some reported reductions in Treg frequency and enhanced effector T cell proliferation.Conclusion: This review highlights that IDO expression in AML is associated with poor prognosis and measurement of IDO and its Kyn metabolites may offer utility as prospective prognostic markers. Pharmacological inhibition of IDO using novel drugs may hold promise for the treatment of AML.

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Clinical and biological implications of mutational spectrum in acute myeloid leukemia of FAB subtypes M4 and M5

Cited by 11 publications

References 33 publications

Up‐regulation of DDIT4 predicts poor prognosis in acute myeloid leukaemia

Up‐regulation of DDIT4 predicts poor prognosis in acute myeloid leukaemia

Upregulation of Glutamic-Oxaloacetic Transaminase 1 Predicts Poor Prognosis in Acute Myeloid Leukemia

Investigating the Role of Indoleamine 2,3-Dioxygenase in Acute Myeloid Leukemia: A Systematic Review

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