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Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in adult T-cell leukemia/lymphoma

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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.
Type: article
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)

Submitter: 中川 雅夫

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