Comprehensive diagnostics of acute myeloid leukemia by whole transcriptome RNA sequencing

Arindrarto, Wibowo; Borràs, Daniel; Groen, Ruben A.L. De; Berg, Redmar R van den; Locher, Irene J.; Diessen, Saskia A.M.E. van; Holst, Rosalie van der; Meijden, Edith D. van der; Honders, M. Willy; Leeuw, Rick H. de; Verlaat, Wina; Jedema, Inge; Kroes, Wilma G. M.; Knijnenburg, Jeroen; Wezel, Tom van; Vermaat, Joost S.P.; Valk, Peter J.M.; Janssen, Bart; Knijff, Peter de; Bergen, Cornelis A.M. van; Akker, Erik B. van den; Hoen, Peter A C ‘t; Kiełbasa, Szymon M.; Laros, Jeroen F. J.; Griffioen, Marieke; Veelken, Hendrik

doi:10.1038/s41375-020-0762-8

Cited by 57 publications

(56 citation statements)

References 49 publications

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“…Acute myeloid leukemia (AML) is a heterogeneous disease of myeloid cells, which is characterized by many different genetic aberrations and requires an increasingly complex approach to treatment [ 1 , 2 ]. Among these aberrations, fusion genes have been frequently and consistently reported [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Targeted Inhibition of the NUP98-NSD1 Fusion Oncogene in Acute Myeloid Leukemia

Mohanty

Jyotsana

Sharma

et al. 2020

Cancers

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NUP98-NSD1-positive acute myeloid leukemia (AML) is a poor prognostic subgroup that is frequently diagnosed in pediatric cytogenetically normal AML. NUP98-NSD1-positive AML often carries additional mutations in genes including FLT3, NRAS, WT1, and MYC. The purpose of our study was to characterize the cooperative potential of the fusion and its associated Neuroblastoma rat sarcoma (NRAS) mutation. By constitutively expressing NUP98-NSD1 and NRASG12D in a syngeneic mouse model and using a patient-derived xenograft (PDX) model from a NUP98-NSD1-positive AML patient, we evaluated the functional role of these genes and tested a novel siRNA formulation that inhibits the oncogenic driver NUP98-NSD1. NUP98-NSD1 transformed murine bone marrow (BM) cells in vitro and induced AML in vivo. While NRASG12D expression was insufficient to transform cells alone, co-expression of NUP98-NSD1 and NRASG12D enhanced the leukemogenicity of NUP98-NSD1. We developed a NUP98-NSD1-targeting siRNA/lipid nanoparticle formulation that significantly prolonged the survival of the PDX mice. Our study demonstrates that mutated NRAS cooperates with NUP98-NSD1 and shows that direct targeting of the fusion can be exploited as a novel treatment strategy in NUP98-NSD1-positive AML patients.

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Section: Introductionmentioning

confidence: 99%

Targeted Inhibition of the NUP98-NSD1 Fusion Oncogene in Acute Myeloid Leukemia

Mohanty

Jyotsana

Sharma

et al. 2020

Cancers

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“…As costs for RNA-seq are decreasing and bioinformatic knowledge and pipelines are being developed 37 , our study shows one of the potential clinical uses of applying RNAseq for AML patients. Other clinical applications of RNAseq include a detailed view of genomic and cytogenetic aberrations as well as the identification of distinct molecular signatures with prognostic and/or predictive impact.…”

Section: Genementioning

confidence: 97%

Integrated transcriptomic and genomic analysis improves prediction of complete remission and survival in elderly patients with acute myeloid leukemia

et al. 2020

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Relevant molecular tools for treatment stratification of patients ≥65 years with acute myeloid leukemia (AML) are lacking. We combined clinical data with targeted DNA-and full RNA-sequencing of 182 intensively and palliatively treated patients to predict complete remission (CR) and survival in AML patients ≥65 years. Intensively treated patients with NPM1 and IDH2 R172 mutations had longer overall survival (OS), whereas mutated TP53 conferred lower CR rates and shorter OS. FLT3-ITD and TP53 mutations predicted worse OS in palliatively treated patients. Gene expression levels most predictive of CR were combined with somatic mutations for an integrated risk stratification that we externally validated using the beatAML cohort. We defined a high-risk group with a CR rate of 20% in patients with mutated TP53, compared to 97% CR in low-risk patients defined by high expression of ZBTB7A and EEPD1 without TP53 mutations. Patients without these criteria had a CR rate of 54% (intermediate risk). The difference in CR rates translated into significant OS differences that outperformed ELN stratification for OS prediction. The results suggest that an integrated molecular risk stratification can improve prediction of CR and OS and could be used to guide treatment in elderly AML patients.

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“…All the clinical, cytogenetic, molecular, and microarray data of these CN-AML patients were obtained from the Gene Expression Omnibus (GEO) database 1 . Overall survival (OS) and event-free survival (EFS) data were obtained from the GEO database and their publications.…”

Section: Patients and Treatmentmentioning

confidence: 99%

“…Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous hematopoietic malignancy. The outcome of AML patients is generally poor and is strongly influenced by gene mutations and chromosomal alterations (1). Currently, the prognostic stratification is based on gene sequencing and cytogenetic analysis.…”

Section: Introductionmentioning

confidence: 99%

Aberrant Chloride Intracellular Channel 4 Expression Is Associated With Adverse Outcome in Cytogenetically Normal Acute Myeloid Leukemia

Huang

Chen

et al. 2020

Front. Oncol.

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Background and Methods: Acute myeloid leukemia (AML), which starts in the bone marrow, is a group of hematopoietic stem cell disorders. Chloride intracellular channel 4 (CLIC4) is regulated by p53, c-Myc, and TGF-β. It induces the NF-κB-dependent activation of HIF (hypoxia-inducible factor) and participates in tumor growth through its microenvironmental function. However, its prognostic value in AML remains unclear, as well as its co-expression biomarkers. In this study, we evaluated the prognostic significance of CLIC4 expression using two independent large cohorts of cytogenetically normal AML (CN-AML) patients. Multivariable analysis and multi-omics analysis with weighted correlation network analysis (WGCNA) in the CN-AML group were also presented. Based on CLIC4 and its related genes, microRNA-target gene interaction network analysis and downstream gene ontology analysis were performed to unveil the complex functions behind CLIC4. Results: We demonstrated that the overexpression of CLIC4 was notably associated with unfavorable outcome in the two independent cohorts of CN-AML patients [overall survival (OS) and event-free survival (EFS): P < 0.0001, n = 185; OS: P = 0.016, n = 232], as well as in the European LeukemiaNet (ELN) Intermediate-I group (OS: P = 0.015, EFS: P = 0.012, n = 115), the National Comprehensive Cancer Network Intermediate Risk AML group (OS and EFS: P < 0.0001, n = 225), and the non-M3 AML group (OS and EFS: P < 0.0001, n = 435). Multivariable analysis further validated CLIC4 as a highrisk factor in the CN-AML group. Multi-omics analysis presented the overexpression of CLIC4 as associated with the co-expression of the different gene sets in leukemia, up/downregulation of the immune-related pathways, dysregulation of microRNAs, and hypermethylation around the CpG islands, in open sea regions, and in different gene structural fragments including TSS1500, gene body, 5 UTR region, 3 UTR region, and the first exon. By further performing WGCNA on multi-omics data, certain biomarkers that are co-expressed with CLIC4 were also unveiled.

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Comprehensive diagnostics of acute myeloid leukemia by whole transcriptome RNA sequencing

Cited by 57 publications

References 49 publications

Targeted Inhibition of the NUP98-NSD1 Fusion Oncogene in Acute Myeloid Leukemia

Targeted Inhibition of the NUP98-NSD1 Fusion Oncogene in Acute Myeloid Leukemia

Integrated transcriptomic and genomic analysis improves prediction of complete remission and survival in elderly patients with acute myeloid leukemia

Aberrant Chloride Intracellular Channel 4 Expression Is Associated With Adverse Outcome in Cytogenetically Normal Acute Myeloid Leukemia

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