LEF-1 is a prosurvival factor in chronic lymphocytic leukemia and is expressed in the preleukemic state of monoclonal B cell lymphocytosis

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BlankBlood First Edition Paper, prepublished online July 1, 2010; DOI

10.1182/blood-2010-02-269878

LEF-1 is a prosurvival factor in chronic lymphocytic leukemia and is expressed

in the preleukemic state of monoclonal B cell lymphocytosis

Albert Gutierrez, Jr.1, C. Tschumper1, Xiaosheng Wu1, Tait D. Shanafelt2,

Jeanette Eckel-Passow3, M. Huddleston, III4, L. Slager3, Neil E. Kay2

and Diane F. Jelinek1,*

1 Department of Immunology, Mayo Clinic, College of Medicine, Rochester, MN,

United States; 2 Department of Internal Medicine, Mayo Clinic, College of

Medicine, Rochester, MN, United States; 3 Department of Health Sciences

Research, Mayo Clinic, College of Medicine, Rochester, MN, United States; 4

Department of Orthopedic Surgery, Mayo Clinic, College of Medicine, Rochester,

MN, United States

* Corresponding author; email: jelinek.diane@...

Abstract

The canonical Wnt signaling pathway is pathogenic in a variety of cancers. We

previously identified aberrant expression of the Wnt pathway transcription

factor and target gene lymphoid enhancer binding factor 1 (LEF-1) in chronic

lymphocytic leukemia (CLL). This suggested that the Wnt signaling pathway has a

role in the biology of CLL. In this study, we performed a Wnt pathway analysis

using gene expression profiling (GEP) and identified aberrant regulation of Wnt

pathway target genes, ligands, and signaling members in CLL cells. Furthermore,

we identified aberrant protein expression of LEF-1 specifically in CLL but not

in normal mature B cell subsets or post B cell activation. Using the TCF/LEF

dual luciferase reporter assay, we demonstrated constitutive Wnt pathway

activation in CLL, while the pathway was inactive in normal peripheral B cells.

Importantly, LEF-1 knockdown decreased CLL B cell survival. We also identified

LEF-1 expression in CD19+/CD5+ cells obtained from patients with monoclonal B

cell lymphocytosis (MBL), suggesting a role for LEF-1 early in CLL

leukemogenesis. This study has identified the constitutive activation and

pro-survival function of LEF-1 and the Wnt pathway in CLL and uncovered a

possible role for these factors in the preleukemic state of MBL.