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

Jo Ishizawa, Eiji Sugihara, Shinji Kuninaka, Kaoru Mogushi, Kensuke Kojima, Christopher B. Benton, Ran Zhao, Dhruv Chachad, Norisato Hashimoto, Rodrigo O. Jacamo, Yihua Qiu, Suk Young Yoo, Shinichiro Okamoto, Michael Andreeff, Steven M. Kornblau, Hideyuki Saya

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish
Pages (from-to)1958-1968
Number of pages11
JournalBlood
Volume129
Issue number14
DOIs
Publication statusPublished - 2017 Apr 6

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B-Cell Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
DNA Damage
B-Lymphocytes
Cells
DNA
Tumors
Anaphase-Promoting Complex-Cyclosome
Proteins
Oncogene Proteins
Cell death
Ligases
Ubiquitin
Cell Cycle
Carcinogenesis
Genes
Chemical activation
Radiation
Neoplasms
Protein Array Analysis

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

FZR1 loss increases sensitivity to DNA damage and consequently promotes murine and human B-cell acute leukemia. / Ishizawa, Jo; Sugihara, Eiji; Kuninaka, Shinji; Mogushi, Kaoru; Kojima, Kensuke; Benton, Christopher B.; Zhao, Ran; Chachad, Dhruv; Hashimoto, Norisato; Jacamo, Rodrigo O.; Qiu, Yihua; Yoo, Suk Young; Okamoto, Shinichiro; Andreeff, Michael; Kornblau, Steven M.; Saya, Hideyuki.

In: Blood, Vol. 129, No. 14, 06.04.2017, p. 1958-1968.

Research output: Contribution to journalArticle

Ishizawa, J, Sugihara, E, Kuninaka, S, Mogushi, K, Kojima, K, Benton, CB, Zhao, R, Chachad, D, Hashimoto, N, Jacamo, RO, Qiu, Y, Yoo, SY, Okamoto, S, Andreeff, M, Kornblau, SM & Saya, H 2017, 'FZR1 loss increases sensitivity to DNA damage and consequently promotes murine and human B-cell acute leukemia', Blood, vol. 129, no. 14, pp. 1958-1968. https://doi.org/10.1182/blood-2016-07-726216
Ishizawa J, Sugihara E, Kuninaka S, Mogushi K, Kojima K, Benton CB et al. FZR1 loss increases sensitivity to DNA damage and consequently promotes murine and human B-cell acute leukemia. Blood. 2017 Apr 6;129(14):1958-1968. https://doi.org/10.1182/blood-2016-07-726216
Ishizawa, Jo ; Sugihara, Eiji ; Kuninaka, Shinji ; Mogushi, Kaoru ; Kojima, Kensuke ; Benton, Christopher B. ; Zhao, Ran ; Chachad, Dhruv ; Hashimoto, Norisato ; Jacamo, Rodrigo O. ; Qiu, Yihua ; Yoo, Suk Young ; Okamoto, Shinichiro ; Andreeff, Michael ; Kornblau, Steven M. ; Saya, Hideyuki. / FZR1 loss increases sensitivity to DNA damage and consequently promotes murine and human B-cell acute leukemia. In: Blood. 2017 ; Vol. 129, No. 14. pp. 1958-1968.
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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

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