FZR1 loss increases sensitivity to DNA damage and consequently promotes murine and human B-cell acute leukemia

Abstract

FZR1 (fizzy-related protein homolog; also known as CDH1 [cell division cycle 20 related 1]) functions in the cell cycle as a specific activator of anaphase-promoting complex or cyclosome ubiquitin ligase, regulating late mitosis, G₁ phase, and activation of the G₂-M checkpoint. FZR1 has been implicated as both a tumor suppressor and oncoprotein, and its precise contribution to carcinogenesis remains unclear. Here, we examined the role of FZR1 in tumorigenesis and cancer therapy by analyzing tumor models and patient specimens. In an <i>Fzr1</i> gene-trap mouse model of B-cell acute lymphoblastic leukemia (B-ALL), mice with <i>Fzr1</i>-deficient B-ALL survived longer than those with <i>Fzr1</i>-intact disease, and sensitivity of <i>Fzr1</i>-deficient B-ALL cells to DNA damage appeared increased. Consistently, conditional knockdown of FZR1 sensitized human B-ALL cell lines to DNA damage-induced cell death. Moreover, multivariate analyses of reverse-phase protein array of B-ALL specimens from newly diagnosed B-ALL patients determined that a low FZR1 protein expression level was an independent predictor of a longer remission duration. The clinical benefit of a low FZR1 expression level at diagnosis was no longer apparent in patients with relapsed B-ALL. Consistent with this result, secondary and tertiary mouse recipients of <i>Fzr1</i>-deficient B-ALL cells developed more progressive and radiation-resistant disease than those receiving <i>Fzr1</i>-intact B-ALL cells, indicating that prolonged inactivation of <i>Fzr1</i> promotes the development of resistant clones. Our results suggest that reduction of FZR1 increases therapeutic sensitivity of B-ALL and that transient rather than tonic inhibition of FZR1 may be a therapeutic strategy.