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

Takashi Ishio; Sarvesh Kumar; Joji Shimono; Anusara Daenthanasanmak; Sigrid Dubois; Yuquan Lin; Bonita Bryant; Michael N. Petrus; Emmanuel Bachy; Da Wei Huang; Yandan Yang; Patrick L. Green; Hiroo Hasegawa; Michiyuki Maeda; Hideki Goto; Tomoyuki Endo; Takashi Yokota; Kanako C. Hatanaka; Yutaka Hatanaka; Shinya Tanaka; Yoshihiro Matsuno; Yibin Yang; Satoshi Hashino; Takanori Teshima; Thomas A. Waldmann; Louis M. Staudt; Masao Nakagawa

doi:10.1182/blood.2021012734

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

Takashi Ishio, Sarvesh Kumar, Joji Shimono, Anusara Daenthanasanmak, Sigrid Dubois, Yuquan Lin, Bonita Bryant, Michael N. Petrus, Emmanuel Bachy, Da Wei Huang, Yandan Yang, Patrick L. Green, Hiroo Hasegawa, Michiyuki Maeda, Hideki Goto, Tomoyuki Endo, Takashi Yokota, Kanako C. Hatanaka, Yutaka Hatanaka, Shinya TanakaYoshihiro Matsuno, Yibin Yang, Satoshi Hashino, Takanori Teshima, Thomas A. Waldmann, Louis M. Staudt, Masao Nakagawa

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

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.

Original language	English
Pages (from-to)	1541-1556
Number of pages	16
Journal	Blood
Volume	139
Issue number	10
DOIs	https://doi.org/10.1182/blood.2021012734
State	Published - Mar 10 2022

Keywords

Adult
Apoptosis/genetics
Cyclin-Dependent Kinase 6/genetics
Humans
Leukemia-Lymphoma, Adult T-Cell/drug therapy
Lymphoma
Mechanistic Target of Rapamycin Complex 1/metabolism
Signal Transduction

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10.1182/blood.2021012734

Cite this

Ishio, T., Kumar, S., Shimono, J., Daenthanasanmak, A., Dubois, S., Lin, Y., Bryant, B., Petrus, M. N., Bachy, E., Huang, D. W., Yang, Y., Green, P. L., Hasegawa, H., Maeda, M., Goto, H., Endo, T., Yokota, T., Hatanaka, K. C., Hatanaka, Y., ... Nakagawa, M. (2022). Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in adult T-cell leukemia/lymphoma. Blood, 139(10), 1541-1556. https://doi.org/10.1182/blood.2021012734

@article{efd9c49bcce64268b7e8115ee3b79622,

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

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.",

keywords = "Adult, Apoptosis/genetics, Cyclin-Dependent Kinase 6/genetics, Humans, Leukemia-Lymphoma, Adult T-Cell/drug therapy, Lymphoma, Mechanistic Target of Rapamycin Complex 1/metabolism, Signal Transduction",

author = "Takashi Ishio and Sarvesh Kumar and Joji Shimono and Anusara Daenthanasanmak and Sigrid Dubois and Yuquan Lin and Bonita Bryant and Petrus, {Michael N.} and Emmanuel Bachy and Huang, {Da Wei} and Yandan Yang and Green, {Patrick L.} and Hiroo Hasegawa and Michiyuki Maeda and Hideki Goto and Tomoyuki Endo and Takashi Yokota and Hatanaka, {Kanako C.} and Yutaka Hatanaka and Shinya Tanaka and Yoshihiro Matsuno and Yibin Yang and Satoshi Hashino and Takanori Teshima and Waldmann, {Thomas A.} and Staudt, {Louis M.} and Masao Nakagawa",

note = "Publisher Copyright: {\textcopyright} 2022 American Society of Hematology",

year = "2022",

month = mar,

day = "10",

doi = "10.1182/blood.2021012734",

language = "English",

volume = "139",

pages = "1541--1556",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

number = "10",

}

Ishio, T, Kumar, S, Shimono, J, Daenthanasanmak, A, Dubois, S, Lin, Y, Bryant, B, Petrus, MN, Bachy, E, Huang, DW, Yang, Y, Green, PL, Hasegawa, H, Maeda, M, Goto, H, Endo, T, Yokota, T, Hatanaka, KC, Hatanaka, Y, Tanaka, S, Matsuno, Y, Yang, Y, Hashino, S, Teshima, T, Waldmann, TA, Staudt, LM & Nakagawa, M 2022, 'Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in adult T-cell leukemia/lymphoma', Blood, vol. 139, no. 10, pp. 1541-1556. https://doi.org/10.1182/blood.2021012734

TY - JOUR

T1 - Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in adult T-cell leukemia/lymphoma

AU - Ishio, Takashi

AU - Kumar, Sarvesh

AU - Shimono, Joji

AU - Daenthanasanmak, Anusara

AU - Dubois, Sigrid

AU - Lin, Yuquan

AU - Bryant, Bonita

AU - Petrus, Michael N.

AU - Bachy, Emmanuel

AU - Huang, Da Wei

AU - Yang, Yandan

AU - Green, Patrick L.

AU - Hasegawa, Hiroo

AU - Maeda, Michiyuki

AU - Goto, Hideki

AU - Endo, Tomoyuki

AU - Yokota, Takashi

AU - Hatanaka, Kanako C.

AU - Hatanaka, Yutaka

AU - Tanaka, Shinya

AU - Matsuno, Yoshihiro

AU - Yang, Yibin

AU - Hashino, Satoshi

AU - Teshima, Takanori

AU - Waldmann, Thomas A.

AU - Staudt, Louis M.

AU - Nakagawa, Masao

PY - 2022/3/10

Y1 - 2022/3/10

N2 - 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.

AB - 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.

KW - Adult

KW - Apoptosis/genetics

KW - Cyclin-Dependent Kinase 6/genetics

KW - Humans

KW - Leukemia-Lymphoma, Adult T-Cell/drug therapy

KW - Lymphoma

KW - Mechanistic Target of Rapamycin Complex 1/metabolism

KW - Signal Transduction

UR - http://www.scopus.com/inward/record.url?scp=85125866810&partnerID=8YFLogxK

U2 - 10.1182/blood.2021012734

DO - 10.1182/blood.2021012734

M3 - Article

C2 - 34818414

SN - 0006-4971

VL - 139

SP - 1541

EP - 1556

JO - Blood

JF - Blood

IS - 10

ER -

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

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

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