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Blood, 1 December 2004, Vol. 104, No. 12, pp. 3437-3444. Prepublished online as a Blood First Edition Paper on August 10, 2004; DOI 10.1182/blood-2004-06-2234. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-06-2234v1 104/12/3437    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Cook, W. D. Articles by Adams, J. M. Search for Related Content PubMed PubMed Citation Articles by Cook, W. D. Articles by Adams, J. M. Related Collections Hematopoiesis and Stem Cells Neoplasia Plenary Papers Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PLENARY PAPERS PU.1 is a suppressor of myeloid leukemia, inactivated in mice by gene deletion and mutation of its DNA binding domain Wendy D. Cook, Benjamin J. McCaw, Christopher Herring, Deborah L. John, Simon J. Foote, Stephen L. Nutt, and Jerry M. Adams From the Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. In most myeloid leukemias induced in mice by -radiation, one copy of chromosome 2 has suffered a deletion. To search for a potential tumor suppressor gene in that region, we have delineated the deletions in a panel of these tumors. A commonly deleted region of 2 megabase pairs (Mbp) includes the gene encoding the PU.1 transcription factor, a powerful inducer of granulocytic/monocytic differentiation. Significantly, in 87% of these tumors the remaining PU.1 allele exhibited point mutations in the PU.1 DNA binding domain. Surprisingly, 86% of these mutations altered a single CpG, implicating deamination of deoxycytidine, a common mutational mechanism, as the origin of this lesion. The "hot spot" resides in the codon for a contact residue essential for DNA binding by PU.1. In keeping with a tumor suppressor role for PU.1, enforced expression of wild-type PU.1 in the promyelocytic leukemia cells inhibited their clonogenic growth, induced monocytic differentiation, and elicited apoptosis. The mutant PU.1 found in tumors retained only minimal growth suppressive function. The results suggest that PU.1 normally suppresses development of myeloid leukemia by promoting differentiation and that the combination of gene deletion and a point mutation that impairs its ability to bind DNA is particularly leukemogenic. 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