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Prepublished online as a Blood First Edition Paper on July 10, 2003; DOI 10.1182/blood-2003-02-0618.
Submitted February 25, 2003
Accepted June 18, 2003
RUNX/AML and C/EBP factors regulate CD11a integrin expression in myeloid cells through overlapping regulatory elements
Amaya Puig-Kroger, Tilman Sanchez-Elsner, Natividad Ruiz, Enrique J Andreu, Felipe Prosper, Uffe B Jensen, Juana Gil, Paul Erickson, Harry Drabkin, Yoram Groner, and Angel L Corbi*
Centro de Investigaciones Biologicas, Madrid, Spain
Clinica Universitaria, Navarra, Spain
Institute of Human Genetics, Aarhus, Denmark
Hospital Universitario Gregorio Maranon, Madrid, Spain
University of Colorado Health Sciences Center, Denver, CO, USA
Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel
* Corresponding author; email: acorbi{at}cib.csic.es.
The CD11a/CD18 (LFA-1) integrin mediates critical leukocyte adhesive interactions during immune and inflammatory responses. The CD11a promoter directs CD11a/CD18 integrin expression and its activity in lymphoid cells depends on a functional RUNX1/AML-1-binding site (AML-110) within the MS7 sequence. We now report that MS7 contains an C/EBP-binding site (C/EBP-100), which overlaps with AML-110 and is bound by C/EBP factors in myeloid cells. C/EBP and RUNX/AML factors compete for binding to their respective cognate elements, and bind to the CD11a promoter MS7 sequence in a cell lineage- and differentiation-dependent manner. In myeloid cells MS7 is primarily recognized by C/EBP factors in proliferating cells whereas RUNX/AML factors (specially RUNX3/AML-2) bind to MS7 in differentiated cells. RUNX3/AML-2 binding to the CD11a promoter correlates with increased RUNX3/AML-2 protein levels and enhanced CD11a/CD18 cell surface expression. The relevance of the AML-110 element is underscored by the ability of AML-1/ETO to inhibit CD11a promoter activity, thus explaining the low CD11a/CD18 expression in t(8;21)-containing myeloid leukemic cells. Therefore, the expression of the CD11a/CD18 integrin in myeloid cells is determined through the differential occupancy of the CD11a proximal promoter by transcription factors implicated in the pathogenesis of myeloid leukemia.
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