1: FZR1 loss increases sensitivity to DNA damage and consequently promotes murine and human B-cell acute leukemia
Science of the Month - June 2017
BLOOD
129 (14):1958-1968; 10.1182/blood-2016-07-726216 APR 6 2017
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
Abnormalities in the cell cycle and DNA repair are observed in many cancers, but how do they affect cancer development and progression? To answer this fundamental and important question, we conducted a seven-year collaborative study with the MD Anderson Cancer Center and have now published some extremely interesting results. First, using a mouse model of adult B-cell acute lymphoblastic leukemia (B-ALL), we deleted FZR1, a molecule involved in the cell cycle and DNA repair. We found that compared to cases with normal FZR1, the sensitivity of B-ALL cells to anticancer drugs and DNA damage stress increased, resulting in improved survival prognosis for the B-ALL mice. Supporting this, an analysis of protein samples and clinical data from approximately 200 B-ALL patients revealed that lower levels of FZR1 were associated with a better response to initial treatment and a tendency to maintain a disease-free state for a longer period. However, importantly, we also found that long-term FZR1 deletion carries the risk of conversely increasing the malignancy of B-ALL. This study not only suggests a potential factor for predicting sensitivity to anticancer drugs but also highlights the significance and risks of DNA repair molecule inhibitors, which have shown promise for development in the cancer field in recent years.
(Jo Ishizawa [83rd class], Department of Leukemia, MD Anderson Cancer Center,
Hideyuki Saya [equivalent to 60th class], Division of Gene Regulation, Institute for Advanced Medical Research)
Other Published Papers
1: Splicing variation of Long-IRBIT determines the target selectivity of IRBIT family proteins
PNAS
114 (15):3921-3926; 10.1073/pnas.1618514114 APR 11 2017
Kawaai, Katsuhiro; Ando, Hideaki; Satoh, Nobuhiko; Yamada, Hideomi; Ogawa, Naoko; Hirose, Matsumi; Mizutani, Akihiro; Bonneau, Benjamin; Seki, George; Mikoshiba, Katsuhiko