AML Subtype Is a Major Determinant of the Association between Prognostic Gene Expression Signatures and Their Clinical Significance

Wiggers, Caroline R.M.; Baak, Mirna; Sonneveld, Edwin; Nieuwenhuis, Edward E. S.; Bartels, Marije; Creyghton, Menno P.

doi:10.1016/j.celrep.2019.08.012

Cited by 13 publications

(12 citation statements)

References 66 publications

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“…refs. 16,17 ). To the best of our knowledge, the largest published transcriptomic studies to date on patient-matched diagnosis-relapse samples comprised 24 adult 18 , respectively 23 pediatric 19 AML cases, with both of these studies being either partially or entirely based on microarrays, which do not allow for detection of various molecular aberrations.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic analysis reveals proinflammatory signatures associated with acute myeloid leukemia progression

et al. 2022

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During the last decade, numerous studies have been carried out to exploit the complexity of genomic and transcriptomic lesions driving acute myeloid leukemia (AML) initiation. These studies have helped improve risk classification and treatment options. Detailed molecular characterization of longitudinal AML samples are, however, sparse, meanwhile relapse and therapy resistance represent the main challenge in AML care. To this end, we performed transcriptome-wide RNA sequencing of longitudinal diagnosis, relapse and/or primary resistant samples from 47 adult and 23 pediatric AML patients with known mutational background. Gene expression analysis revealed the association of short event-free survival with overexpression of GLI2 and IL1R1, as well as downregulation of ST18. Moreover, CR1-downregulation and DPEP1-upregulation were associated with AML relapse both in adults and children. Finally, machine learning and network-based analysis identified overexpressed CD6 and downregulated INSR as highly co-predictive genes depicting important relapse-associated characteristics among adult AML patients. Our findings point towards the importance of a tumor-promoting inflammatory environment in leukemia progression, as indicated by several of the herein identified differentially expressed genes. Together, this knowledge provides the foundation for novel personalized drug targets and has the potential to maximize the benefit of current treatments, to improve cure rates in AML.

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Section: Introductionmentioning

confidence: 99%

Transcriptomic analysis reveals proinflammatory signatures associated with acute myeloid leukemia progression

et al. 2022

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“…While the FAB-type specificity was very pronounced for differential splicing profiles, it also affected differential gene expression profiles. For instance, the upregulation of MEIS1 and FOXC1, previously reported to be associated with mutated NPM1 and to regulate stem-like properties [31], was only noted in the FLT3-ITD+/NPM1+ samples of M1 and M2 FAB types, but not in M4 specimens. These observations indicate that the relevance of differential splicing and expression of important contributors to leukemogenesis is limited to certain differentiation stages of AML.…”

Section: Discussionmentioning

confidence: 85%

“…Therefore, the aim of this study was to explore the differential splicing profiles associated with the presence of FLT3-ITD with concomitant NPM1 mutations to characterize their potential oncogenic relevance. Furthermore, AS profiles as well as gene expression profiles orchestrate differentiation and maturation of cells and tissues and therefore, can show much variability between various cell types and maturation stadia [30,31]. Since both FLT3-ITD and NPM1 mutations occur in AML cells arrested in different maturation stadia, we evaluated whether differential splicing and differential expression signatures in relation to FLT3-ITD and NPM1 mutations in AML showed FAB subtype specificity.…”

Section: Introductionmentioning

confidence: 99%

Maturation State-Specific Alternative Splicing in FLT3-ITD and NPM1 Mutated AML

Wojtuszkiewicz

Werf

Hütter

et al. 2021

Cancers

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Despite substantial progress achieved in unraveling the genetics of AML in the past decade, its treatment outcome has not substantially improved. Therefore, it is important to better understand how genetic mutations translate to phenotypic features of AML cells to further improve response predictions and to find innovative therapeutic approaches. In this respect, aberrant splicing is a crucial contributor to the pathogenesis of hematological malignancies. Thus far, altered splicing is well characterized in relation to splicing factor mutations in AML. However, splicing profiles associated with mutations in other genes remain largely unexplored. In this study, we explored differential splicing profiles associated with two of the most common aberrations in AML: FLT3-ITD and NPM1 mutations. Using RNA-sequencing data of a total of 382 primary AML samples, we found that the co-occurrence of FLT3-ITD and mutated NPM1 is associated with differential splicing of FAB-type specific gene sets. Despite the FAB-type specificity of particular gene sets, the primary functions perturbed by differential splicing in all three FAB types include cell cycle control and DNA damage response. Interestingly, we observed functional divergence between alternatively spliced and differentially expressed genes in FLT3-ITD+/NPM1+ samples in all analyzed FAB types, with differential expression affecting genes involved in hematopoietic differentiation. Altogether, these observations indicate that concomitant FLT3-ITD and mutated NPM1 are associated with the maturation state-specific differential splicing of genes with potential oncogenic relevance.

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“…AML is the most common hematologic malignancy, with multiple molecular subtypes and cellular heterogeneity [24]. Over the last decade, significant efforts have been made to elucidate the molecular changes in genome-wide profiling involved in AML oncogenesis.…”

Section: Discussionmentioning

confidence: 99%

Clusterization in acute myeloid leukemia based on prognostic alternative splicing signature to reveal the clinical characteristics in the bone marrow microenvironment

Zhang

Chen

et al. 2020

Cell Biosci

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Background Alternative splicing (AS), a crucial post-transcriptional regulatory mechanism in expanding the coding capacities of genomes and increasing the diversity of proteins, still faces various challenges in the splicing regulation mechanism of acute myeloid leukemia (AML) and microenvironmental changes. Results A total of 27,833 AS events were detected in 8337 genes in 178 AML patients, with exon skip being the predominant type. Approximately 11% of the AS events were significantly related to prognosis, and the prediction models based on various events demonstrated high classification efficiencies. Splicing factors correlation networks further altered the diversity of AS events through epigenetic regulation and clarified the potential mechanism of the splicing pathway. Unsupervised cluster analysis revealed significant correlations between AS and immune features, molecular mutations, immune checkpoints and clinical outcome. The results suggested that AS clusters could be used to identify patient subgroups with different survival outcomes in AML, among which C1 was both associated with good outcome in overall survival. Interestingly, C1 was associated with lower immune scores compared with C2 and C3, and favorable-risk cytogenetics was rarely distributed in C2, but much more common in C1. Conclusions This study revealed a comprehensive landscape of AS events, and provides new insight into molecular targeted therapy and immunotherapy strategy for AML.

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AML Subtype Is a Major Determinant of the Association between Prognostic Gene Expression Signatures and Their Clinical Significance

Cited by 13 publications

References 66 publications

Transcriptomic analysis reveals proinflammatory signatures associated with acute myeloid leukemia progression

Transcriptomic analysis reveals proinflammatory signatures associated with acute myeloid leukemia progression

Maturation State-Specific Alternative Splicing in FLT3-ITD and NPM1 Mutated AML

Clusterization in acute myeloid leukemia based on prognostic alternative splicing signature to reveal the clinical characteristics in the bone marrow microenvironment

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