Promoter demethylation of the asparagine synthetase gene is required for ATF4-dependent adaptation to asparagine depletion Gene Regulation

Tumor cells adapt to nutrient-limited environments by inducing gene expression that ensures adequate nutrients to sustain metabolic demands. For example, during amino acid limitations, ATF4 in the amino acid response induces expression of asparagine synthetase (ASNS), which provides for asparagine biosynthesis. Acute lymphoblastic leukemia (ALL) cells are sensitive to asparagine depletion, and administration of the asparagine depletion enzyme l-asparaginase is an important therapy option. ASNS expression can counterbalance l-asparaginase treatment by mitigating nutrient stress. Therefore, understanding the mechanisms regulating ASNS expression is important to define the adaptive processes underlying tumor progression and treatment. Here we show that DNA hypermethylation at the ASNS promoter prevents its transcriptional expression following asparagine depletion. Insufficient expression of ASNS leads to asparagine deficiency, which facilitates ATF4-independent induction of CCAAT-enhancer-binding protein homologous protein (CHOP), which triggers apoptosis. We conclude that chromatin accessibility is critical for ATF4 activity at the ASNS promoter, which can switch ALL cells from an ATF4-dependent adaptive response to ATF4-independent apoptosis during asparagine depletion. This work may also help explain why ALL cells are most sensitive to l-asparaginase treatment compared with other cancers.
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Cell Biology Source Type: research

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Malavasi CD22 is a surface molecule expressed early during the ontogeny of B cells in the bone marrow and spleen, and can be found on B cells isolated from the different lymphoid compartments in humans. CD22 is expressed by most blasts from the majority (60–90%) of B-cell acute lymphoblastic leukemia (B-ALL). Current therapies in adults with newly diagnosed B-ALL are associated with complete remission (CR) rates of 50–90%. However, 30–60% of these patients relapse, and only 25–40% achieve disease-free survival of three years or more. Chemotherapy regimens for patients with re...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
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Source: Cancer and Metastasis Reviews - Category: Cancer & Oncology Source Type: research
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Source: Pharmaceutical Research - Category: Drugs & Pharmacology Source Type: research
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Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research
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Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
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Source: Cancer and Metastasis Reviews - Category: Cancer & Oncology Source Type: research
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Source: Toxicology in Vitro - Category: Toxicology Authors: Tags: Toxicol In Vitro Source Type: research
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Source: Ecancermedicalscience - Category: Cancer & Oncology Tags: Ecancermedicalscience Source Type: research
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Source: Supportive Care in Cancer - Category: Cancer & Oncology Source Type: research
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Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
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