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Loss of MLL PHD finger 3 is necessary for MLL-ENL-induced hematopoietic stem cell immortalization
Journal article   Open access   Peer reviewed

Loss of MLL PHD finger 3 is necessary for MLL-ENL-induced hematopoietic stem cell immortalization

Jing Chen, Donna A. Santillan, Mark Koonce, Wei Wei, Roger Luo, Michael Thirman, Nancy J Zeleznik-Le and Manuel O Diaz
Cancer research, Vol.68(15), pp.6199-6207
08/01/2008
DOI: 10.1158/0008-5472.CAN-07-6514
PMID: 18676843
url
https://doi.org/10.1158/0008-5472.CAN-07-6514View
Published (Version of record) Open Access

Abstract

Reciprocal chromosomal translocations at the MLL gene locus result in expression of novel fusion proteins, such as MLL-ENL, associated with leukemia. The three PHD finger cassette, one of the highly conserved domains in MLL, is absent in all fusion proteins. This domain has been shown to interact with Cyp33, a cyclophilin which enhances the recruitment of histone deacetylases (HDAC) to the MLL repression domain and mediates HOX gene repression. Insertion of the third PHD finger of MLL into MLL-ENL allows the recruitment of Cyp33 and, subsequently, HDAC1 to the fusion protein. Furthermore, expression of the fusion protein with the PHD finger insertion mediates the down-regulation of the HOXC8 gene expression in a Cyp33-dependent manner. Finally, the addition of the PHD finger domain or the third PHD finger alone into MLL-ENL blocks the hematopoietic stem cell immortalization potential of the fusion protein in serial plating colony assays. Insertion of only the first and second PHD fingers has no such effect. These data support the hypothesis that the binding of Cyp33 to the MLL third PHD finger switches the MLL function from transactivation to repression. In the immortalizing MLL fusion protein, the loss of the PHD fingers, in combination with the gain of the activation domain of ENL or of other partner proteins, makes the fusion protein a constitutive transactivator. This leads to constitutive overexpression of MLL target genes that block stem cell commitment and promote stem cell renewal, probably the first step in MLL-related leukemogenesis.
 RNA Obstetrics and Gynecology Animals Base Sequence Cell Line Cell Transformation Neoplastic Cyclophilins/metabolism DNA Primers Hematopoietic Stem Cells/cytology Histone Deacetylase 1 Histone Deacetylases/metabolism Homeodomain Proteins/genetics Humans Mice Myeloid-Lymphoid Leukemia Protein/chemistry/genetics/physiology Messenger/genetics Retroviridae/genetics Reverse Transcriptase Polymerase Chain Reaction

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