Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in adult T-cell leukemia/lymphoma
| Autor: | Yandan Yang, Sigrid Dubois, Takashi Ishio, Takanori Teshima, Shinya Tanaka, Emmanuel Bachy, Masao Nakagawa, Satoshi Hashino, Yibin Yang, Sarvesh Kumar, Yutaka Hatanaka, Anusara Daenthanasanmak, Joji Shimono, Tomoyuki Endo, Patrick L. Green, Bonita R. Bryant, Yoshihiro Matsuno, Michiyuki Maeda, Hiroo Hasegawa, Da-Wei Huang, Michael N. Petrus, Thomas A. Waldmann, Yuquan Lin, Takashi Yokota, Hideki Goto, Kanako C. Hatanaka, Louis M. Staudt |
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| Rok vydání: | 2022 |
| Předmět: |
Adult
Cell cycle checkpoint Lymphoma Immunology Apoptosis mTORC1 Mechanistic Target of Rapamycin Complex 1 Palbociclib Malignancy Biochemistry Adult T-cell leukemia/lymphoma immune system diseases hemic and lymphatic diseases medicine Humans Leukemia-Lymphoma Adult T-Cell biology Cyclin-Dependent Kinase 6 Cell Biology Hematology medicine.disease Leukemia Cancer research biology.protein Cyclin-dependent kinase 6 Signal Transduction |
| Zdroj: | Blood. 139:1541-1556 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.2021012734 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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