Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia
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ABSTRACT:
PROVIDER: PRJNA1049463 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27118425_1.fastq.gz | Fastqsanger.gz | |||
| SRR27118425_2.fastq.gz | Fastqsanger.gz | |||
| SRR27118426_1.fastq.gz | Fastqsanger.gz | |||
| SRR27118426_2.fastq.gz | Fastqsanger.gz | |||
| SRR27118427_1.fastq.gz | Fastqsanger.gz |
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Project description:Mutation in nucleophosmin (NPM1) causes relocalization of this normally nucleolar protein to the cytoplasm (NPM1c+). Despite NPM1 mutation being the most common driver mutation in cytogenetically normal adult acute myeloid leukemia (AML), the mechanisms of NPM1c+-induced leukemogenesis remain unclear. Caspase-2 is a proapoptotic protein activated by NPM1 in the nucleolus. Here, we show that caspase-2 is also activated by NPM1c+ in the cytoplasm and DNA damage-induced apoptosis is caspase-2 dependent in NPM1c+ but not in NPM1wt AML cells. Strikingly, in NPM1c+ cells, caspase-2 loss results in profound cell cycle arrest, differentiation, and down-regulation of stem cell pathways that regulate pluripotency including impairment of the AKT/mTORC1 pathways, and inhibition of Rictor cleavage. In contrast, there were minimal differences in proliferation, differentiation, or the transcriptional profile of NPM1wt cells lacking caspase-2. Our results show that caspase-2 is essential for proliferation and self-renewal of AML cells expressing mutated NPM1. This study demonstrates that caspase-2 is a major effector of NPM1c+ function.
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Project description:Multilineage dysplasia (MLD) has no impact on biological, clinico-pathological and prognostic features of AML with mutated nucleophosmin (NPM1) NPM1-mutated AML is a provisional entity in the WHO-2008 classification of myeloid neoplasms. The significance of concomitant multilineage dysplasia (MLD) in NPM1-mutated AML is unclear. Thus, in the WHO-2008 classification, NPM1-mutated AML with MLD is classified as AML with myelodysplasia(MD)-related changes. We evaluated the MLD impact in 378 NPM1-mutated AML patients. MLD was found in about 25% cases. Except for a lower WBC and FLT3-ITD incidence in MLD+ group, no significant differences were observed in age, sex, cytogenetics and FLT3-TKD between NPM1-mutated AML with and without MLD. Notably, NPM1-mutated AML with/without MLD showed overlapping immunophenotype (CD34-negativity) and GEP (CD34 downregulation and HOX genes upregulation). Moreover, OS and EFS did not differ among NPM1-mutated AML patients, independently of whether they carried or not MLD, the NPM1-mutated/FLT3-ITD negative cases showing the better prognosis. Lack of MLD impact on survival was confirmed by multivariate analysis that highlighted FLT3-ITD as the most significant prognostic parameter in NPM1-mutated AML. Our findings indicate that NPM1 mutations rather than MLD dictate the distinctive features of NPM1-mutated AML. Thus, irrespective of MLD, NPM1-mutated AML should be considered as one disease entity clearly distinct from AML with MD-related changes. These findings have important diagnostic and prognostic implications in AML. All 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. 48 samples
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