title: 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, G1phase, 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 anFzr1gene-trap mouse model of B-cell acute lymphoblastic leukemia (B-ALL), mice withFzr1-deficient B-ALL survived longer than those withFzr1-intact disease, and sensitivity ofFzr1-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 ofFzr1-deficient B-ALL cells developed more progressive and radiation-resistant disease than those receivingFzr1-intact B-ALL cells, indicating that prolonged inactivation ofFzr1promotes 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.
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, and.|Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.|Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Jo
authors.initials: J
authors.lastname: Ishizawa
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, and.
authors.forename: Eiji
authors.initials: E
authors.lastname: Sugihara
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, and.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kuninaka
authors.affiliation: Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Mogushi
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.|Hematology, Respiratory Medicine, and Oncology, Department of Medicine, Saga University, Saga, Japan; and.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kojima
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Benton
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Ran
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Dhruv
authors.initials: D
authors.lastname: Chachad
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, and.|Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Norisato
authors.initials: N
authors.lastname: Hashimoto
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Rodrigo O
authors.initials: RO
authors.lastname: Jacamo
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Suk Young
authors.initials: SY
authors.lastname: Yoo
authors.affiliation: Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, and.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
mesh_terms: D000818:Animals; D064200:Cdh1 Proteins / Q000096:biosynthesis / Q000235:genetics; D016923:Cell Death; D004249:DNA Damage; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy
chemical_list: D064200:Cdh1 Proteins; C577584:FZR1 protein, human; C577585:Fzr1 protein, mouse; D009363:Neoplasm Proteins