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 Blood, 1 November 2008, Vol. 112, No. 9, pp. 3777-3787.
Prepublished online as a Blood First Edition Paper on August 11, 2008; DOI 10.1182/blood-2008-01-134122.

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NEOPLASIA

PEBP2-β/CBF-β–dependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis

Hee-Jun Wee1, Dominic Chih-Cheng Voon1, Suk-Chul Bae2, and Yoshiaki Ito1,3

1 Genomics and Genetics Division, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Proteos, Singapore; 2 Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University, Cheongju, South Korea; and 3 Oncology Research Institute, Centre for Life Sciences, National University of Singapore, Singapore

The heterodimeric transcription factor RUNX1/PEBP2-β (also known as AML1/CBF-β) is essential for definitive hematopoiesis. Here, we show that interaction with PEBP2-β leads to the phosphorylation of RUNX1, which in turn induces p300 phosphorylation. This is mediated by homeodomain interacting kinase 2 (HIPK2), targeting Ser249, Ser273, and Thr276 in RUNX1, in a manner that is also dependent on the RUNX1 PY motif. Importantly, we observed the in vitro disruption of this phosphorylation cascade by multiple leukemogenic genetic defects targeting RUNX1/CBFB. In particular, the oncogenic protein PEBP2-β-SMMHC prevents RUNX1/p300 phosphorylation by sequestering HIPK2 to mislocalized RUNX1/β-SMMHC complexes. Therefore, phosphorylation of RUNX1 appears a critical step in its association with and phosphorylation of p300, and its disruption may be a common theme in RUNX1-associated leukemogenesis.


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