KDM4B promotes acute myeloid leukemia associated with AML1-ETO by regulating chromatin accessibility

Area of Science:

• Epigenetics
• Cancer Biology
• Hematology

Background:

• Epigenetic modifications, including chromatin accessibility, are crucial in cancer development.
• Lysine demethylase 4B (KDM4B) is an epigenetic modifier with histone demethylase activity implicated in solid tumors.
• The specific role and context dependency of KDM4B in hematological malignancies remain underexplored.

Purpose of the Study:

• To investigate the role of KDM4B in acute myeloid leukemia (AML), particularly in cases with the t(8;21) chromosomal translocation.
• To elucidate the molecular mechanisms by which KDM4B contributes to leukemogenesis in this specific AML subtype.

Main Methods:

• Analysis of clinical sample gene expression profiles to identify KDM4B upregulation in t(8;21) AML.
• Short hairpin RNA (shRNA)-mediated KDM4B silencing in AML cell lines.
• Investigation of KDM4B's effect on gene expression, chromatin accessibility, and enhancer marks.
• Functional studies using murine KDM4B orthologue mutants.
• Generation and analysis of Kdm4b conditional knockout mice.

Main Results:

• KDM4B expression is specifically elevated in AML associated with the t(8;21) translocation, which generates the AML1-ETO fusion oncogene.
• KDM4B silencing significantly inhibits proliferation of t(8;21) AML cells and suppresses AML1-ETO-inducible genes.
• KDM4B depletion perturbs chromatin accessibility at AML1-ETO binding sites, altering active enhancer marks.
• KDM4B's methylated-histone binding modules are essential for proliferation.
• Kdm4b deficiency in mice attenuates AML1-ETO-mediated clonogenic potential and delays leukemia progression.

Conclusions:

• KDM4B plays a significant tumor-promoting role in AML with the t(8;21) translocation.
• Targeting KDM4B may represent a therapeutic strategy for this specific subtype of AML.