Dysregulation of Frizzled 6 is a critical component of B-cell leukemogenesis in a mouse model of chronic lymphocytic leukemia

• Published in: Blood 2009-03, Vol.113 (13), p.3031-3039
• Main Authors: Wu, Qing-Li, Zierold, Claudia, Ranheim, Erik A.
• Format: Article
• Language: English
• Subjects: Animals; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; beta Catenin - genetics; beta Catenin - metabolism; Cell Transformation, Neoplastic - genetics; Disease Models, Animal; Frizzled Receptors - genetics; Frizzled Receptors - metabolism; Frizzled Receptors - physiology; Gene Expression Regulation, Leukemic - physiology; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Lymphoid Neoplasia; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Receptors, G-Protein-Coupled - physiology; Signal Transduction - genetics; Wnt Proteins - genetics; Wnt Proteins - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-06-163303

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 β-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, before 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. We find that, in the course of leukemogenesis, the expression of Wnt16, Wnt10α, Fzd1, and most dramatically, Fzd6, is progressively up-regulated in the transformed CD5+ B cells of these mice, as are β-catenin protein levels. Elimination of Fzd6 expression by crossing into Fzd6−/− mice significantly delays development of chronic lymphocytic leukemia 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.