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.

中文翻译：

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全基因组 CRISPR 筛选将 CDK6 确定为成人 T 细胞白血病/淋巴瘤的治疗靶点。

成人 T 细胞白血病/淋巴瘤 (ATLL) 是一种侵袭性 T 细胞恶性肿瘤，目前的治疗预后不佳。在这里，我们报告了 ATLL 模型的全基因组 CRISPR-Cas9 筛选，确定了 CDK6、CCND2、BATF3、JUNB、STAT3 和 IL10RB 是 ATLL 细胞增殖和/或存活所必需的基因。作为单一药物，CDK6 抑制剂 palbociclib 在具有野生型 TP53 的 ATLL 模型中诱导细胞周期停滞和细胞凋亡。由于代偿性 CDK2 活性，从基因上灭活 TP53 的 ATLL 模型对 palbociclib 具有相对抗性，并且这种抗性可以被突变体 TP53 的小分子激活剂 APR-246 逆转。CRISPR-Cas9 屏幕进一步突出了 ATLL 细胞对 mTORC1 信号的依赖性。无论 TP53 状态如何，使用 palbociclib 联合 mTORC1 抑制剂治疗 ATLL 细胞都具有协同毒性。这项工作将 CDK6 定义为 ATLL 的新治疗靶点，并支持 palbociclib 联合 mTORC1 抑制剂在这种顽固性恶性肿瘤中的临床评估。