Submitted June 16, 2008
Accepted January 14, 2009
Dysregulation of frizzled 6 is a critical component of B cell leukemogenesis in a mouse model of chronic lymphocytic leukemia
Qing-Li Wu, Claudia Zierold, and Erik A. Ranheim*
Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
* Corresponding author; email: earanheim{at}wisc.edu.
Wnt/Fzd signaling is known to play a key role in development, tissue specific stem cell maintenance, and tumorigenesis, particularly through the canonical pathway involving stabilization of 
-catenin. We have previously shown that Fzd9-/- mice have a deficiency in pre-B cells at a stage when self-renewing division is occurring in preference to further differentiation, prior to light chain immunoglobulin recombination. To determine whether pathologic usurpation of this pathway plays a role in B cell leukemogenesis, we examined the expression of Wnt/Fzd pathway genes in the Eµ-TCL1 mouse model of chronic lymphocytic leukemia (CLL). We find that in the course of leukemogenesis, the expression of Wnt16, Wnt10b, Fzd1, and most dramatically, Fzd6, are progressively upregulated in the transformed CD5+ B cells of these mice, as are -catenin protein levels. Elimination of Fzd6 expression by crossing into Fzd6-/- mice significantly delays development of CLL in this model. Our findings suggest that the self-renewal signals mediated by Wnt/Fzd that are enlisted during B cell development may be pathologically reactivated in the neoplastic transformation of mature B cells.
