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ECSASB2 mediates MLL degradation during hematopoietic differentiation
Jingya Wang1, Andrew G Muntean, Jay L Hess
1Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Blood
|December 17, 2011
Summary
ASB2 targets Mixed lineage leukemia (MLL) for degradation, impacting hematopoietic differentiation. MLL fusion proteins lacking specific regions resist this degradation, potentially contributing to leukemia development.
Area of Science:
- Molecular Biology
- Hematopoiesis
- Cancer Biology
Background:
- Mixed lineage leukemia (MLL) is crucial for hematopoietic development.
- Chromosomal translocations involving MLL are common in human leukemia.
Purpose of the Study:
- To investigate the role of ASB2 in MLL regulation.
- To understand the mechanism of MLL degradation and its impact on hematopoietic differentiation.
Main Methods:
- Investigated ASB2 interaction with MLL using biochemical assays.
- Assessed MLL degradation and transactivation activity upon ASB2 expression.
- Examined MLL fusion protein stability and ASB2 interaction.
- Analyzed ASB2 expression during hematopoietic differentiation.
- Utilized ASB2 knockdown to study effects on HOXA9 and cell differentiation.
Main Results:
- ASB2 mediates MLL degradation via interaction with the MLL PHD/Bromodomain.
- Forced ASB2 expression reduces MLL levels and transactivation.
- MLL-AF9 fusion proteins are resistant to ASB2-mediated degradation.
- ASB2 expression increases during differentiation, correlating with MLL decrease.
- ASB2 knockdown elevates HOXA9 and delays differentiation.
Conclusions:
- ASB2 promotes hematopoietic differentiation by degrading MLL and down-regulating HOX genes.
- Resistance of MLL fusion proteins to ASB2 degradation, due to PHD/Bromo region alterations, may drive leukemogenesis.
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