Dataset Information

Characterization of somatic mutation-associated microenvironment signatures in acute myeloid leukemia patients based on TCGA analysis.

ABSTRACT: Recurrent genetic mutations occur in acute myeloid leukemia (AML) and have been incorporated into risk stratification to predict the prognoses of AML patients. The bone marrow microenvironment plays a critical role in the development and progression of AML. However, the characteristics of the genetic mutation-associated microenvironment have not been comprehensively identified to date. In this study, we obtained the gene expression profiles of 173 AML patients from The Cancer Genome Atlas (TCGA) database and calculated their immune and stromal scores by applying the ESTIMATE algorithm. Immune scores were significantly associated with OS and cytogenetic risk. Next, we categorized the intermediate and poor cytogenetic risk patients into individual-mutation and wild-type groups according to RUNX1, ASXL1, TP53, FLT3-ITD, NPM1 and biallelic CEBPA mutation status. The relationships between the immune microenvironment and each genetic mutation were investigated by identifying differentially expressed genes (DEGs) and conducting functional enrichment analyses of them. Significant immune- and stromal-relevant DEGs associated with each mutation were identified, and most of the DEGs (from the FLT3-ITD, NPM1 and biallelic CEBPA mutation groups) were validated in the GSE14468 cohort downloaded from the Gene Expression Omnibus (GEO) database. In summary, we identified key immune- and stromal-relevant gene signatures associated with genetic mutations in AML, which may provide new biomarkers for risk stratification and personalized immunotherapy.

SUBMITTER: Wang J

PROVIDER: S-EPMC7643165 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Characterization of somatic mutation-associated microenvironment signatures in acute myeloid leukemia patients based on TCGA analysis.

Wang Jun J Dao Feng-Ting FT Yang Lu L Qin Ya-Zhen YZ

Scientific reports 20201104 1

Recurrent genetic mutations occur in acute myeloid leukemia (AML) and have been incorporated into risk stratification to predict the prognoses of AML patients. The bone marrow microenvironment plays a critical role in the development and progression of AML. However, the characteristics of the genetic mutation-associated microenvironment have not been comprehensively identified to date. In this study, we obtained the gene expression profiles of 173 AML patients from The Cancer Genome Atlas (TCGA) ...[more]

PMID: 33149230

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Project description:Simple Summary Despite remarkable progress in the outcome of childhood acute myeloid leukemia (AML), risk of relapse and refractory diseases remains high. Treatment of the chemo-refractory disease is restricted by dose-limiting therapy-related toxicities which necessitate alternative tolerable efficient therapeutic modalities. By disrupting its immune environment, leukemic blasts are known to gain the ability to evade immune surveillance and promote disease progression; therefore, many efforts have been made to redirect the immune system against malignant blasts. Deeper knowledge about immunologic alterations has paved the way to the discovery and development of novel targeted therapeutic concepts, which specifically override the immune evasion mechanisms to eradicate leukemic blasts. Herein, we review innovative immunotherapeutic strategies and their mechanisms of action in pediatric AML. Abstract Acute myeloid leukemia is a life-threatening malignant disorder arising in a complex and dysregulated microenvironment that, in part, promotes the leukemogenesis. Treatment of relapsed and refractory AML, despite the current overall success rates in management of pediatric AML, remains a challenge with limited options considering the heavy but unsuccessful pretreatments in these patients. For relapsed/refractory (R/R) patients, hematopoietic stem cell transplantation (HSCT) following ablative chemotherapy presents the only opportunity to cure AML. Even though in some cases immune-mediated graft-versus-leukemia (GvL) effect has been proven to efficiently eradicate leukemic blasts, the immune- and chemotherapy-related toxicities and adverse effects considerably restrict the feasibility and therapeutic power. Thus, immunotherapy presents a potent tool against acute leukemia but needs to be engineered to function more specifically and with decreased toxicity. To identify innovative immunotherapeutic approaches, sound knowledge concerning immune-evasive strategies of AML blasts and the clinical impact of an immune-privileged microenvironment is indispensable. Based on our knowledge to date, several promising immunotherapies are under clinical evaluation and further innovative approaches are on their way. In this review, we first focus on immunological dysregulations contributing to leukemogenesis and progression in AML. Second, we highlight the most promising therapeutic targets for redirecting the leukemic immunosuppressive microenvironment into a highly immunogenic environment again capable of anti-leukemic immune surveillance.

Project description:Acute myeloid leukemia (AML) is a very heterogeneous and highly malignant blood cancer. Mutations of the DNA methyltransferase DNMT3A are among the most frequent recurrent genetic lesions in AML. The majority of DNMT3A-mutant AML patients shows fast relapse and poor survival, but also patients with long survival or long-term remission have been reported. Underlying molecular signatures and mechanisms that contribute to these survival differences are only poorly understood and have not been studied in detail so far. We applied hierarchical clustering to somatic gene mutation profiles of 51 DNMT3A-mutant patients from The Cancer Genome Atlas (TCGA) AML cohort revealing two robust patient subgroups with profound differences in survival. We further determined molecular signatures that distinguish both subgroups. Our results suggest that FLT3 and/or NPM1 mutations contribute to survival differences of DNMT3A-mutant patients. We observed an upregulation of genes of the p53, VEGF and DNA replication pathway and a downregulation of genes of the PI3K-Akt pathway in short- compared to long-lived patients. We identified that the majority of measured miRNAs was downregulated in the short-lived group and we found differentially expressed microRNAs between both subgroups that have not been reported for AML so far (miR-153-2, miR-3065, miR-95, miR-6718) suggesting that miRNAs could be important for prognosis. In addition, we learned gene regulatory networks to predict potential major regulators and found several genes and miRNAs with known roles in AML pathogenesis, but also interesting novel candidates involved in the regulation of hematopoiesis, cell cycle, cell differentiation, and immunity that may contribute to the observed survival differences of both subgroups and could therefore be important for prognosis. Moreover, the characteristic gene mutation and expression signatures that distinguished short- from long-lived patients were also predictive for independent DNMT3A-mutant AML patients from other cohorts and could also contribute to further improve the European LeukemiaNet (ELN) prognostic scoring system. Our study represents the first in-depth computational approach to identify molecular factors associated with survival differences of DNMT3A-mutant AML patients and could trigger additional studies to develop robust molecular markers for a better stratification of AML patients with DNMT3A mutations.

Dataset Information

Characterization of somatic mutation-associated microenvironment signatures in acute myeloid leukemia patients based on TCGA analysis.

Publications

Characterization of somatic mutation-associated microenvironment signatures in acute myeloid leukemia patients based on TCGA analysis.

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