HBO1-MLL interaction promotes AF4/ENL/P-TEFb-mediated leukemogenesis.

Area of Science:

• Hematology
• Molecular Biology
• Cancer Research

Background:

• Leukemic oncoproteins drive uncontrolled hematopoietic progenitor self-renewal through aberrant gene activation, leading to leukemia.
• The precise molecular mechanisms behind this aberrant gene activation remain incompletely understood.

Purpose of the Study:

• To elucidate the molecular mechanism by which MLL fusion proteins cause aberrant gene activation in leukemia.
• To investigate the role of the HBO1 histone acetyltransferase complex in MLL-mediated leukemogenesis.

Main Methods:

• Co-immunoprecipitation assays to assess protein-protein interactions between MLL fusion proteins and the HBO1 complex.
• Chromatin immunoprecipitation followed by sequencing (ChIP-seq) to analyze histone modifications and gene expression.
• Functional assays in murine hematopoietic progenitors to evaluate leukemic transformation.

Main Results:

• Leukemic MLL fusion proteins bind to the HBO1 histone acetyltransferase (HAT) complex via their trithorax homology domain 2 (THD2).
• This interaction is mediated by ING4/5 and PHF16 subunits of HBO1 within a chromatin context marked by H3K4 tri-methylation.
• MLL-ELL specifically requires THD2-HBO1 interaction for leukemic transformation, facilitating the recruitment of the AF4/ENL/P-TEFb (AEP) complex to target gene promoters.
• NUP98-HBO1 fusion protein promotes oncogenesis through MLL interaction, independent of its HAT activity.

Conclusions:

• The interaction between MLL fusion proteins and the HBO1 complex is a critical nexus in leukemic transformation.
• This MLL-HBO1 interaction represents a potential therapeutic target for developing novel anti-leukemia drugs.