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Prepublished online as a Blood First Edition Paper on November 21, 2002; DOI 10.1182/blood-2002-06-1664.
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Blood, 15 March 2003, Vol. 101, No. 6, pp. 2355-2362
NEOPLASIA
ELL-associated factor 2 (EAF2), a functional homolog of EAF1 with
alternative ELL binding properties
Federico Simone,
Roger T. Luo,
Paul E. Polak,
Joseph J. Kaberlein, and
Michael J. Thirman
From the University of Chicago Section of
Hematology/Oncology, Chicago, IL.
The (11;19)(q23;p13.1) translocation in acute leukemia results in
the formation of an MLL-ELL fusion protein. ELL is an RNA polymerase II
elongation factor that interacts with the recently identified EAF1
protein. To characterize the normal functions of ELL and its aberrant
activities when fused to MLL, we isolated a second protein that
interacts with ELL named EAF2 for ELL
Associated Factor 2. EAF2 is highly
homologous to EAF1, with 58% identity and 74% amino acid
conservation. Using specific antibodies generated to EAF2, we
coimmunoprecipitated ELL and EAF2 from multiple cell lines. Confocal
microscopy revealed that endogenous EAF2 and ELL colocalized in a
nuclear speckled pattern. Database comparisons with EAF2 identified a
region with a high content of serine, aspartic acid, and glutamic acid
residues that is conserved with EAF1 and exhibited amino acid
similarity with several translocation partner proteins of MLL,
including AF4 and ENL. We found that EAF2 and EAF1 both contain
transcriptional activation domains within this region. Using retroviral
bone marrow transduction, we observed that a heterologous fusion of
EAF2 to MLL immortalized hematopoietic progenitor cells. In contrast to
EAF1, EAF2 does not bind to the carboxy-terminus of ELL. We identified
a protein-protein interaction domain within the amino-terminus of ELL
that binds to both EAF1 and EAF2. This amino-terminal interaction
domain is disrupted in the formation of the MLL-ELL fusion protein.
Thus, MLL-ELL retains an interaction domain for EAF1 but not for EAF2.
Taken together, these data suggest that MLL-ELL may disrupt the normal protein-protein interactions of ELL.
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