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Single-cell transcriptome analyses reveal critical roles of RNA splicing during leukemia progression

ABSTRACT: Firstly, we extracted bone marrow cells from AML mouse models in four different timepoints (T0, T1, T2 and T3). And we used droplet-based single cell RNA sequencing technology to reveal the early-MDS, late-MDS, MDS-AML and AML four-stage landscape in a mouse AML model initiated by Myc overexpression. Also, we extracted one AML patient bone marrow sample to sequence by constructing library following 10X genomics platform. And integrated this data with four AML patients data from 10X genomics database to explain the molecular mechanism of splicing events of TMEM134 in AML. To verify the alternative splicing results, we used smartseq2 to construct the single cell library in T3. And combined TCGA-LAML and TARGET-AML database and our mouse function data, we identify the alternative splicing events of TMEM134 could drive the proliferation function in acute myelogenous leukemogenesis.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE142645 | GEO | 2023/01/30

REPOSITORIES: GEO

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Project description:Full Title: Multilineage Dysplasia (MLD) in AML correlates with MDS-related cytogenetic abnormalities and a prior history of MDS or MDS/MPN but has no independent prognostic relevance: A comparison of 408 cases classified as “AML not otherwise specified” or “AML with myelodysplasia-related changes” The WHO classification of acute myeloid leukemia (AML) is hierarchically structured and integrates genetic information, data on patients’ history, and multilineage dysplasia (MLD). The category “AML with MDS-related changes” (AML-MRC) is separated from AML not otherwise specified (AML-NOS) by the presence of either MLD, MDS-related cytogenetics or MDS history. To clarify whether MLD alone is clinically relevant, we analyzed 408 adult patients categorized as AML-MRC or AML-NOS. EFS (Median 13.8 months vs. 16.0 months) and 3-year-OS (45.8% vs. 53.9%) did not differ significantly between patients with MLD and without. However, MLD correlated with pre-existing MDS (p<0.001) and MDS-related cytogenetics (p=0.035). Patients with MLD as sole AML-MRC criterion (AML-MLD-sole; n=90) had less frequently FLT3-ITD (p=0.032), and a lower median age than AML-NOS (n=232), but EFS, OS, and WBC did not differ significantly. Contrarily, patients with AML-NOS plus AML-MLD-sole (n=323) versus patients with MDS history or MDS-related cytogenetics (n=85) had better EFS (16.9 vs. 10.7 months; p=0.005) and 3-year-OS (55.8% vs. 32.5%; p=0.001). Gene expression profiles were measured for a subset of 96 patients. Analysis of the expression data showed distinct clusters for AML-MLD-sole and AML-NOS versus AML with MDS-related cytogenetics or MDS history. Thus, MLD demonstrated no independent clinical impact, while cytogenetics and MDS history were of prognostic relevance. This data suggest modifications in a revised WHO proposal. All 96 bone marrow samples were obtained from untreated patients at the time of diagnosis. Cells used for microarray analysis were collected from the purified fraction of mononuclear cells after Ficoll density centrifugation.

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Single-cell transcriptome analyses reveal critical roles of RNA splicing during leukemia progression

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