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The PHD fingers of MLL block MLL fusion protein-mediated transformation.

ABSTRACT: Chromosomal translocations involving the mixed lineage leukemia (MLL) gene are associated with aggressive acute lymphoid and myeloid leukemias. These translocations are restricted to an 8.3-kb breakpoint region resulting in fusion of amino terminal MLL sequences in frame to 1 of more than 60 different translocation partners. The translocations consistently delete the plant homeodomain (PHD) fingers and more carboxyl terminal MLL sequences. The function of the PHD fingers is obscure and their specific role in transformation has not been explored. Here we show that inclusion of the PHD fingers in the MLL fusion protein MLL-AF9 blocked immortalization of hematopoietic progenitors. Inclusion of 2 or more PHD fingers reduced association with the Hoxa9 locus and suppressed Hoxa9 up-regulation in hematopoietic progenitors. These data provide an explanation for why MLL translocation breakpoints exclude the PHD fingers and suggest a possible role for these domains in regulating the function of wild-type MLL.

SUBMITTER: Muntean AG

PROVIDER: S-EPMC2597135 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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The PHD fingers of MLL block MLL fusion protein-mediated transformation.

Muntean Andrew G AG Giannola Diane D Udager Aaron M AM Hess Jay L JL

Blood 20080916 12

Chromosomal translocations involving the mixed lineage leukemia (MLL) gene are associated with aggressive acute lymphoid and myeloid leukemias. These translocations are restricted to an 8.3-kb breakpoint region resulting in fusion of amino terminal MLL sequences in frame to 1 of more than 60 different translocation partners. The translocations consistently delete the plant homeodomain (PHD) fingers and more carboxyl terminal MLL sequences. The function of the PHD fingers is obscure and their spe ...[more]

PMID: 18796627

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Protein interactions of the MLL PHD fingers modulate MLL target gene regulation in human cells.

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Diverse functions of PHD fingers of the MLL/KMT2 subfamily.

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PHD fingers: epigenetic effectors and potential drug targets.

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Structural insight into histone recognition by the ING PHD fingers.

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