Title: | Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in adult T-cell leukemia/lymphoma |
Authors: | Ishio, Takashi Browse this author |
Kumar, Sarvesh Browse this author |
Shimono, Joji Browse this author |
Daenthanasanmak, Anusara Browse this author |
Dubois, Sigrid Browse this author |
Lin, Yuquan Browse this author |
Bryant, Bonita Browse this author |
Petrus, Michael N. Browse this author |
Bachy, Emmanuel Browse this author |
Huang, Da Wei Browse this author |
Yang, Yandan Browse this author |
Green, Patrick L. Browse this author |
Hasegawa, Hiroo Browse this author |
Maeda, Michiyuki Browse this author |
Goto, Hideki Browse this author |
Endo, Tomoyuki Browse this author |
Yokota, Takashi Browse this author →KAKEN DB |
Hatanaka, Kanako C. Browse this author |
Hatanaka, Yutaka Browse this author →KAKEN DB |
Tanaka, Shinya Browse this author →KAKEN DB |
Matsuno, Yoshihiro Browse this author →KAKEN DB |
Yang, Yibin Browse this author |
Hashino, Satoshi Browse this author |
Teshima, Takanori Browse this author →KAKEN DB |
Waldmann, Thomas A. Browse this author |
Staudt, Louis M. Browse this author |
Nakagawa, Masao Browse this author →KAKEN DB |
Issue Date: | 10-Mar-2022 |
Publisher: | American Society of Hematology |
Journal Title: | Blood |
Volume: | 139 |
Issue: | 10 |
Start Page: | 1541 |
End Page: | 1556 |
Publisher DOI: | 10.1182/blood.2021012734 |
Abstract: | Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy with a poor prognosis with current therapy. Here we report genome-wide CRISPR-Cas9 screening of ATLL models, which identified CDK6, CCND2, BATF3, JUNB, STAT3, and IL10RB as genes that are essential for the proliferation and/or survival of ATLL cells. As a single agent, the CDK6 inhibitor palbociclib induced cell cycle arrest and apoptosis in ATLL models with wild-type TP53. ATLL models that had inactivated TP53 genetically were relatively resistant to palbociclib owing to compensatory CDK2 activity, and this resistance could be reversed by APR-246, a small molecule activator of mutant TP53. The CRISPR-Cas9 screen further highlighted the dependence of ATLL cells on mTORC1 signaling. Treatment of ATLL cells with palbociclib in combination with mTORC1 inhibitors was synergistically toxic irrespective of the TP53 status. This work defines CDK6 as a novel therapeutic target for ATLL and supports the clinical evaluation of palbociclib in combination with mTORC1 inhibitors in this recalcitrant malignancy. |
Rights: | http://creativecommons.org/licenses/by-nc-nd/4.0/ |
Type: | article |
URI: | http://hdl.handle.net/2115/88267 |
Appears in Collections: | 医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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