ANP32B-mediated repression of p53 contributes to maintenance of normal and CML stem cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA764729 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15980106_1.fastq.gz | Fastqsanger.gz | |||
| SRR15980106_2.fastq.gz | Fastqsanger.gz | |||
| SRR15980107_1.fastq.gz | Fastqsanger.gz | |||
| SRR15980107_2.fastq.gz | Fastqsanger.gz | |||
| SRR15980108_1.fastq.gz | Fastqsanger.gz |
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Project description:we demonstrate that conditional deletion of acidic leucine-rich nuclear phosphoprotein 32B (ANP32B) in hematopoietic cells impairs repopulation capacity and postinjury regeneration of HSCs. Mechanistically, ANP32B forms a repressive complex with and thus inhibits the transcriptional activity of p53 in hematopoietic cells, and p53 deletion rescues the functional defect in Anp32b-deficient HSCs. Of great interest, ANP32B is highly expressed in leukemic cells from patients with chronic myelogenous leukemia (CML). Anp32b deletion enhances p53 transcriptional activity to impair LSC function in a murine CML model and exhibits synergistic therapeutic effects with tyrosine kinase inhibitors in inhibiting CML propagation. In summary, our findings provide a novel strategy to enhance p53 activity in LSCs by inhibiting ANP32B and identify ANP32B as a potential therapeutic target in treating CML.
2021-09-27 | GSE184474 | GEO
Project description:Proper regulation of p53 signaling is critical for the maintenance of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). The hematopoietic cell-specific mechanisms regulating p53 activity remain largely unknown. Here, we demonstrate that conditional deletion of acidic leucine-rich nuclear phosphoprotein 32B (ANP32B) in hematopoietic cells impairs repopulation capacity and postinjury regeneration of HSCs. Mechanistically, ANP32B forms a repressive complex with p53 and thus inhibits the transcriptional activity of p53 in hematopoietic cells, and p53 deletion rescues the functional defect in Anp32b-deficient HSCs. Of great interest, ANP32B is highly expressed in leukemic cells from patients with chronic myelogenous leukemia (CML). Anp32b deletion enhances p53 transcriptional activity to impair LSC function in a murine CML model and exhibits synergistic therapeutic effects with tyrosine kinase inhibitors in inhibiting CML propagation. In summary, our findings provide a novel strategy to enhance p53 activity in LSCs by inhibiting ANP32B and identify ANP32B as a potential therapeutic target in treating CML.
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Project description:In this report, we revealed that branched chain amino acid transaminase 1 (BCAT1) is highly enriched in both mouse and human TKI-resistant CML cells. Leukemia was almost completely abrogated upon BCAT1 knockdown during transplantation in a BCR-ABLT315I-induced murine TKI-resistant CML model . Moreover, knockdown of BCAT1 led to a dramatic decrease in the proliferation of TKI-resistant human leukemia cell lines. BCAA/BCAT1 signaling enhanced the phosphorylation of CREB, which is required for maintenance of TKI-resistant CML cells. Importantly, blockade of BCAA/BCAT1 signaling efficiently inhibited leukemogenesis both in vivo and in vitro.
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Project description:Chronic myeloid leukemia (CML) results from hematopoietic stem cell transformation by the BCR-ABL tyrosine kinase. We have shown that the SIRT1 deacetylase is overexpressed in CML LSC, and may contribute to their maintenance. Here, using genetic deletion of SIRT1 in transgenic CML mice, we definitively demonstrate that SIRT1 is required for leukemia development, and reveal its critical role in mediating increased mitochondrial respiration in CML LSC.
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Project description:ABL1 kinase inhibitors such as imatinib mesylate (IM) are effective in managing chronic myelogenous leukemia (CML) but incapable of eliminating leukemia stem cells (LSCs), suggesting that kinaseM-bM-^HM-^Rindependent pathways support LSC survival. Given that the bone marrow hypoxic microenvironment supports hematopoietic stem cells, we investigated if hypoxia similarly contributes to LSC persistence. Importantly, we found that while BCRM-bM-^HM-^RABL1 kinase remained effectively inhibited by IM under hypoxia, apoptosis became partially suppressed. Furthermore, hypoxia enhanced the clonogenicity of CML cells, as well as their efficiency in repopulating immunodeficient mice, both in the presence and absence of IM. HIF1M-bM-^HM-^RM-NM-1, which is the master regulator of the hypoxia transcriptional response is expressed in the bone marrow specimens of CML individuals. In vitro, HIF1M-bM-^HM-^RM-NM-1 is stabilized during hypoxia and its expression and transcriptional activity can be partially attenuated by concurrent IM treatment. Expression analysis demonstrates at the whole transcriptome level that hypoxia and IM regulate distinct subsets of genes. Functionally, knockdown of HIF1M-bM-^HM-^RM-NM-1 abolished the enhanced clonogenicity during hypoxia. Taken together, our results suggest that in the hypoxic microenvironment, HIF1M-bM-^HM-^RM-NM-1 signaling supports LSC persistence independently of BCRM-bM-^HM-^RABL1 kinase activity. Thus targeting HIF1M-bM-^HM-^RM-NM-1 and its pathway components may be therapeutically important for the complete eradication of LSCs. 24 samples consisting CD34+ bone marrow aspirates of 3 chronic phase patients that were subjected to 24h or 96h of DMSO/Normoxia (21% oxygen, 5% carbon dioxide) control, 2 M-BM-5M Imatinib, hypoxia (0.5% oxygen, 5% carbon dioxide) or combined Imatinib/hypoxia treatments in triplicate cultures.
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