TY - JOUR
T1 - FZR1 loss increases sensitivity to DNA damage and consequently promotes murine and human B-cell acute leukemia
AU - Ishizawa, Jo
AU - Sugihara, Eiji
AU - Kuninaka, Shinji
AU - Mogushi, Kaoru
AU - Kojima, Kensuke
AU - Benton, Christopher B.
AU - Zhao, Ran
AU - Chachad, Dhruv
AU - Hashimoto, Norisato
AU - Jacamo, Rodrigo O.
AU - Qiu, Yihua
AU - Yoo, Suk Young
AU - Okamoto, Shinichiro
AU - Andreeff, Michael
AU - Kornblau, Steven M.
AU - Saya, Hideyuki
N1 - Funding Information:
Conflict-of-interest disclosure: H.S. received research grants from Daiichi Sankyo Inc. and Eisai Co. Ltd. The remaining authors declare no competing financial interests.
Funding Information:
The authors thank K. Yamamura and K. Araki (Kumamoto University, Japan) for kindly providing Fzr1 transgenic mice; M.Nakanishi,K.Nagata,S.Suzuki,I.Ishimatsu,Y.Ito,andS.Hayashi (Keio University) for technical assistance; O. Nagano, T. Shimizu, K. Kai, N. Onishi, and M. Tamada (Keio University) for technical advice; and K. Arai (Keio University, Japan) and D. Norwood (MD Anderson Cancer Center) for help with manuscript preparation. This study was supported in part by a Japan Society for the Promotion of Science Postdoctoral Fellowship for Research Abroad Award (J.I.); the National Institutes of Health, National Cancer Institute (grants CA49639, CA100632, CA136411, and CA16672) and the Paul and Mary Haas Chair in Genetics (M.A.); the Leukemia & Lymphoma Society (grant 6089) (S.M.K.); and a grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (H.S.). This study was also supported in part by research funding from Daiichi Sankyo Inc. and Eisai Co. Ltd. (H.S.).
Publisher Copyright:
© 2017 by The American Society of Hematology.
PY - 2017/4/6
Y1 - 2017/4/6
N2 - 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 Fzr1 gene-trap mouse model of B-cell acute lymphoblastic leukemia (B-ALL), mice with Fzr1-deficient B-ALL survived longer than those with Fzr1-intact disease, and sensitivity of Fzr1-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 Fzr1-deficient B-ALL cells developed more progressive and radiation-resistant disease than those receiving Fzr1-intact B-ALL cells, indicating that prolonged inactivation of Fzr1 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.
AB - 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 Fzr1 gene-trap mouse model of B-cell acute lymphoblastic leukemia (B-ALL), mice with Fzr1-deficient B-ALL survived longer than those with Fzr1-intact disease, and sensitivity of Fzr1-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 Fzr1-deficient B-ALL cells developed more progressive and radiation-resistant disease than those receiving Fzr1-intact B-ALL cells, indicating that prolonged inactivation of Fzr1 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.
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U2 - 10.1182/blood-2016-07-726216
DO - 10.1182/blood-2016-07-726216
M3 - Article
C2 - 28143883
AN - SCOPUS:85027457105
SN - 0006-4971
VL - 129
SP - 1958
EP - 1968
JO - Blood
JF - Blood
IS - 14
ER -