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PU.1 is a suppressor of myeloid leukemia, inactivated in mice by gene deletion and mutation of its DNA binding domain

Citation

Cook, WD and McCaw, BJ and Herring, C and John, DL and Foote, SJ and Nutt, SL and Adams, JM, PU.1 is a suppressor of myeloid leukemia, inactivated in mice by gene deletion and mutation of its DNA binding domain, Blood, 104, (12) pp. 3437-3444. ISSN 0006-4971 (2004) [Refereed Article]

DOI: doi:10.1182/blood-2004-06-2234

Abstract

In most myeloid leukemias induced in mice by γ-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. © 2004 by The American Society of Hematology.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Clinical Sciences
Research Field:Medical Genetics (excl. Cancer Genetics)
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Blood Disorders
Author:Foote, SJ (Professor Simon Foote)
ID Code:34956
Year Published:2004
Web of Science® Times Cited:85
Deposited By:Menzies Centre
Deposited On:2005-08-01
Last Modified:2005-08-01
Downloads:0

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