PRDM16 Suppresses MLL1r Leukemia via Intrinsic Histone Methyltransferase Activity

Area of Science:

• Molecular Biology
• Epigenetics
• Cancer Biology

Background:

• PRDM16 is a known transcription co-factor involved in stem cell maintenance and brown adipose tissue development.
• Its precise role in leukemogenesis and epigenetic regulation remained largely uncharacterized.

Purpose of the Study:

• To investigate the enzymatic activity of PRDM16 and its role in leukemogenesis.
• To elucidate the molecular mechanisms by which PRDM16 exerts its tumor-suppressive functions.

Main Methods:

• Biochemical assays to determine PRDM16's histone methyltransferase activity.
• In vitro and in vivo studies using cell lines and animal models of MLL-AF9-induced leukemia.
• Gene expression analysis and knockdown/overexpression studies of PRDM16 and Gfi1b.

Main Results:

• PRDM16 functions as a histone H3K4 methyltransferase, with its PR domain essential for this activity.
• PRDM16's methyltransferase activity is required for suppressing MLL fusion protein-induced leukemia.
• PRDM16 directly activates Gfi1b, leading to downregulation of the HOXA gene cluster, mediating its tumor suppressor function.
• Silencing of PRDM16 via DNA methylation correlates with MLL-AF9-induced leukemic transformation.

Conclusions:

• PRDM16 possesses a novel histone methyltransferase activity crucial for its tumor suppressor function in leukemia.
• The PR domain-dependent methyltransferase activity of PRDM16 is essential for regulating Gfi1b and HOXA genes, thereby inhibiting leukemogenesis.