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Updated: Oct 12, 2025
Evaluation of Abnormal Growth-related Genes of Hematopoietic Stem and Progenitor Cells by Combining CRISPR/Cas9 Technology with Cell Counting
Published on: May 2, 2025
Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in adult T-cell leukemia/lymphoma
Takashi Ishio1, Sarvesh Kumar2, Joji Shimono1
1Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan.
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.
Insights
Genome-wide screening identified essential genes for Adult T-cell leukemia/lymphoma (ATLL) proliferation. The CDK6 inhibitor palbociclib showed efficacy, especially combined with mTORC1 inhibitors, offering new therapeutic avenues for this aggressive cancer.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy with limited therapeutic options.
- Current treatments for ATLL often result in poor prognoses.
Purpose of the Study:
- To identify novel therapeutic targets and strategies for Adult T-cell leukemia/lymphoma (ATLL) using genome-wide screening.
- To evaluate the efficacy of CDK6 inhibition and combination therapies in ATLL models.
Main Methods:
- Genome-wide CRISPR-Cas9 screening was performed on ATLL models.
- The effects of palbociclib (a CDK6 inhibitor) and APR-246 (a TP53 activator) were assessed.
- Synergistic toxicity of combination therapies, including mTORC1 inhibitors, was investigated.
Main Results:
- CRISPR-Cas9 screening identified CDK6, CCND2, BATF3, JUNB, STAT3, and IL10RB as essential for ATLL cell survival and proliferation.
- Palbociclib induced cell cycle arrest and apoptosis in TP53 wild-type ATLL models.
- Combination therapy with palbociclib and mTORC1 inhibitors demonstrated synergistic toxicity, overcoming TP53-mediated resistance.
Conclusions:
- CDK6 is a novel therapeutic target for Adult T-cell leukemia/lymphoma.
- Combination therapy with palbociclib and mTORC1 inhibitors shows promise for treating ATLL, irrespective of TP53 status.
- Further clinical evaluation of these therapeutic strategies in ATLL is warranted.
