期刊
BLOOD
卷 139, 期 10, 页码 1541-1556出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2021012734
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资金
- Japan Society for the Promotion of Science [JP18K08313, JP21H02775]
- SENSHIN Medical Research Foundation
- Takeda Science Foundation
- National Institutes of Health/National Cancer Institute [CA100730]
- Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research
- EU Transcan-2 consortium ERANET-PLL
The study identifies CDK6 as a novel therapeutic target for adult T-cell leukemia/lymphoma (ATLL) and suggests the potential of combining CDK6 inhibitor palbociclib with mTORC1 inhibitors for treating this difficult malignancy.
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.
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