Glucocorticoids uncover a critical role for ASH2L on BCL-X expression regulation in leukemia cells
Luciana Rocha-Viegas1, Micaela Silbermins1, María Florencia Ogara1
1CONICET-Universidad de Buenos Aires, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), C1428EHA, Buenos Aires, Argentina.
Abstract:
Targeting the apoptosis machinery is a promising therapeutic approach in myeloid malignancies. BCL2L1 is a well-known glucocorticoid-responsive gene and a key apoptosis regulator that, when over-expressed, can contribute to tumor development, progression and therapeutic resistance. Moreover, synthetic glucocorticoids, like dexamethasone, are frequently used in the treatment of hematopoietic diseases due to its pro-apoptotic properties. We report here that the trithorax protein ASH2L, considered one of the core subunits of H3K4-specific MLL/SET methyltransferase complexes, contributes to anti-apoptotic BCL-XL over-expression and cell survival in patient-derived myeloid leukemia cells. We find that the unliganded glucocorticoid receptor (uGR) and ASH2L interact in a common protein complex through a chromatin looping determined by uGR and ASH2L binding to BCL2L1 specific +58 HRE and promoter region, respectively. Upon addition of dexamethasone, GR and ASH2L recruitment is reduced, BCL-XL expression diminishes and apoptosis is induced consequently. Overall, our findings indicate that uGR and ASH2L may act as key regulatory players of BCL- XL upregulation in AML cells.
Insights
The unliganded glucocorticoid receptor (uGR) and ASH2L protein interact to promote BCL-XL overexpression in myeloid leukemia cells. Dexamethasone disrupts this interaction, reducing BCL-XL and inducing apoptosis.
Area of Science:
- Molecular Biology
- Cancer Biology
- Epigenetics
Background:
- Targeting apoptosis is a key strategy for myeloid malignancies.
- BCL2L1 overexpression promotes tumor development and therapeutic resistance.
- Glucocorticoids like dexamethasone are used in treating hematopoietic diseases.
Purpose of the Study:
- To investigate the role of ASH2L in regulating BCL-XL expression and cell survival in myeloid leukemia.
- To elucidate the interaction between the unliganded glucocorticoid receptor (uGR) and ASH2L in controlling BCL-XL.
- To understand the effect of dexamethasone on this regulatory pathway.
Main Methods:
- Chromatin immunoprecipitation (ChIP) assays to detect protein-DNA interactions.
- Co-immunoprecipitation to confirm protein-protein interactions.
- Quantitative PCR and Western blotting to measure gene and protein expression levels.
Main Results:
- ASH2L interacts with uGR in a complex that binds to the BCL2L1 gene promoter and +58 HRE.
- This interaction is associated with increased BCL-XL expression and enhanced survival in patient-derived myeloid leukemia cells.
- Dexamethasone treatment disrupts the uGR-ASH2L complex, leading to decreased BCL-XL levels and induced apoptosis.
Conclusions:
- uGR and ASH2L are key regulators of BCL-XL upregulation in acute myeloid leukemia (AML) cells.
- The interaction between uGR and ASH2L is crucial for maintaining anti-apoptotic BCL-XL expression.
- Disrupting the uGR-ASH2L interaction represents a potential therapeutic strategy for myeloid malignancies.
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