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Updated: Feb 8, 2026
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GPI Anchoring of Proteins in the ER Membrane
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hDOT1L links histone methylation to leukemogenesis
Yuki Okada1, Qin Feng, Yihui Lin
1Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Cell
|April 27, 2005
Summary
Histone methylation by hDOT1L is crucial in human cancer. Mistargeting hDOT1L to Hoxa9 drives MLL-AF10 leukemia, suggesting hDOT1L
Area of Science:
- Epigenetics
- Molecular Biology
- Cancer Research
Background:
- Epigenetic modifications, particularly histone methylation, are implicated in human cancer development.
- Histone methylation by yeast Dot1 and its human homolog, hDOT1L, affects cancer-relevant gene expression.
- hDOT1L methylates lysine 79 on histone H3.
Purpose of the Study:
- To investigate the role of hDOT1L in MLL-AF10-mediated leukemogenesis.
- To elucidate the interaction between hDOT1L and AF10.
- To determine if hDOT1L's methyltransferase activity is essential for leukemic transformation.
Main Methods:
- Investigated the interaction between hDOT1L and AF10 using the OM-LZ region of AF10.
- Created MLL-hDOT1L fusion proteins to assess leukemic transformation.
- Analyzed gene expression (e.g., Hoxa9) and histone methylation (H3-K79) in transformed cells.
Main Results:
- hDOT1L interacts with AF10 via the OM-LZ region, critical for MLL-AF10 leukemogenesis.
- Direct fusion of MLL to hDOT1L causes leukemic transformation dependent on hDOT1L's methyltransferase activity.
- MLL-hDOT1L and MLL-AF10 fusions upregulate leukemia-associated genes like Hoxa9, with increased H3-K79 methylation.
Conclusions:
- Mistargeting of hDOT1L to Hoxa9 is a key mechanism in MLL-AF10-mediated leukemogenesis.
- The enzymatic activity of hDOT1L is essential for leukemic transformation.
- hDOT1L's methyltransferase activity represents a potential therapeutic target for acute myeloid leukemia.
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