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Volume 272, Number 45, Issue of November 7, 1997 pp. 28407-28414
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

HRX Leukemic Fusion Proteins Form a Heterocomplex with the Leukemia-associated Protein SET and Protein Phosphatase 2A

(Received for publication, May 7, 1997, and in revised form, August 29, 1997)

Haskell T. Adler , Ferez S. Nallaseth , Gernot Walter ^¶ and Douglas C. Tkachuk

From the  Veterans Administration Puget Sound Health Care System, Seattle Division, Seattle, Washington 98108, the ^¶ Department of Pathology, University of California at San Diego, La Jolla, California 92093-0612, and the  Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195-7470

One of the most common chromosomal abnormalities in acute leukemia is a reciprocal translocation involving the HRX gene at chromosome locus 11q23, resulting in HRX fusion proteins. Using the yeast two-hybrid system, in vitro binding studies, and human cell culture coimmunoprecipitation experiments, we show here that a region of the HRX protein that is consistently retained in HRX leukemic fusion proteins interacts directly with SET, another protein implicated in leukemia. We have identified the binding sites on HRX for SET and show that these sequences are clustered near the A·T hooks that have been shown to bind DNA. We also show that carboxyl-terminal SET sequences, possibly the acidic tail of SET, bind to HRX. We have also found serine/threonine-specific protein phosphatase activity in anti-HRX coimmunoprecipitates. Using the phosphatase inhibitor okadaic acid and Western blotting, the phosphatase was identified as protein phosphatase 2A (PP2A). Mutation of a single amino acid in one of the SET binding sites of HRX resulted in lower amounts of both coimmunoprecipitated SET protein and coimmunoprecipitated PP2A. These results suggest that the leukemogenic effects of HRX fusion proteins may be related to interactions with SET and PP2A.

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