Pharmacological inactivation of CDK2 inhibits MYC/BCL-XL-driven leukemia in vivo through induction of cellular senescence
Bazzar, Wesam ; Bocci, Matteo LU
; Hejll, Eduar
; Högqvist Tabor, Vedrana
; Hydbring, Per
; Grandien, Alf
; Alzrigat, Mohammad
and Larsson, Lars-Gunnar
(2021)
In Cell Cycle
20(1).
p.23-38
- Abstract
Deregulated expression of the MYC oncogene is a frequent event during tumorigenesis and generally correlates with aggressive disease and poor prognosis. While MYC is a potent inducer of apoptosis, it often suppresses cellular senescence, which together with apoptosis is an important barrier against tumor development. For this latter function, MYC is dependent on cyclin-dependent kinase 2 (CDK2). Here, we utilized a MYC/BCL-XL-driven mouse model of acute myeloblastic leukemia (AML) to investigate whether pharmacological inhibition of CDK2 can inhibit MYC-driven tumorigenesis through induction of senescence. Purified mouse hematopoietic stem cells transduced with MYC and BCL-XL were transplanted into lethally irradiated mice, leading to... (More)
Deregulated expression of the MYC oncogene is a frequent event during tumorigenesis and generally correlates with aggressive disease and poor prognosis. While MYC is a potent inducer of apoptosis, it often suppresses cellular senescence, which together with apoptosis is an important barrier against tumor development. For this latter function, MYC is dependent on cyclin-dependent kinase 2 (CDK2). Here, we utilized a MYC/BCL-XL-driven mouse model of acute myeloblastic leukemia (AML) to investigate whether pharmacological inhibition of CDK2 can inhibit MYC-driven tumorigenesis through induction of senescence. Purified mouse hematopoietic stem cells transduced with MYC and BCL-XL were transplanted into lethally irradiated mice, leading to the development of massive leukemia and subsequent death 15-17 days after transplantation. Upon disease onset, mice were treated with the selective CDK2 inhibitor CVT2584 or vehicle either by daily intraperitoneal injections or continuous delivery via mini-pumps. CVT2584 treatment delayed disease onset and moderately but significantly improved survival of mice. Flow cytometry revealed a significant decrease in tumor load in the spleen, liver and bone marrow of CVT2584-treated compared to vehicle-treated mice. This was correlated with induced senescence evidenced by reduced cell proliferation, increased senescence-associated β-galactosidase activity and heterochromatin foci, expression of p19ARF and p21CIP1, and reduced phosphorylation (activation) of pRb, while very few apoptotic cells were observed. In addition, phosphorylation of MYC at Ser-62 was decreased. In summary, inhibition of CDK2 delayed MYC/BCL-XL-driven AML linked to senescence induction. Our results suggest that CDK2 is a promising target for pro-senescence cancer therapy, in particular for MYC-driven tumors, including leukemia.
(Less)
- author
- Bazzar, Wesam
; Bocci, Matteo
LU
; Hejll, Eduar
; Högqvist Tabor, Vedrana
; Hydbring, Per
; Grandien, Alf
; Alzrigat, Mohammad
and Larsson, Lars-Gunnar
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cell Cycle
- volume
- 20
- issue
- 1
- pages
- 23 - 38
- publisher
- Landes Bioscience
- external identifiers
-
- pmid:33356836
- scopus:85098490742
- ISSN
- 1551-4005
- DOI
- 10.1080/15384101.2020.1855740
- language
- English
- LU publication?
- no
- additional info
- © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
- id
- 4925fb2d-5f0d-4617-a040-553d5b23a029
- date added to LUP
- 2021-01-03 08:33:10
- date last changed
- 2024-06-28 07:16:19
@article{4925fb2d-5f0d-4617-a040-553d5b23a029,
abstract = {{<p>Deregulated expression of the MYC oncogene is a frequent event during tumorigenesis and generally correlates with aggressive disease and poor prognosis. While MYC is a potent inducer of apoptosis, it often suppresses cellular senescence, which together with apoptosis is an important barrier against tumor development. For this latter function, MYC is dependent on cyclin-dependent kinase 2 (CDK2). Here, we utilized a MYC/BCL-XL-driven mouse model of acute myeloblastic leukemia (AML) to investigate whether pharmacological inhibition of CDK2 can inhibit MYC-driven tumorigenesis through induction of senescence. Purified mouse hematopoietic stem cells transduced with MYC and BCL-XL were transplanted into lethally irradiated mice, leading to the development of massive leukemia and subsequent death 15-17 days after transplantation. Upon disease onset, mice were treated with the selective CDK2 inhibitor CVT2584 or vehicle either by daily intraperitoneal injections or continuous delivery via mini-pumps. CVT2584 treatment delayed disease onset and moderately but significantly improved survival of mice. Flow cytometry revealed a significant decrease in tumor load in the spleen, liver and bone marrow of CVT2584-treated compared to vehicle-treated mice. This was correlated with induced senescence evidenced by reduced cell proliferation, increased senescence-associated β-galactosidase activity and heterochromatin foci, expression of p19ARF and p21CIP1, and reduced phosphorylation (activation) of pRb, while very few apoptotic cells were observed. In addition, phosphorylation of MYC at Ser-62 was decreased. In summary, inhibition of CDK2 delayed MYC/BCL-XL-driven AML linked to senescence induction. Our results suggest that CDK2 is a promising target for pro-senescence cancer therapy, in particular for MYC-driven tumors, including leukemia.</p>}},
author = {{Bazzar, Wesam and Bocci, Matteo and Hejll, Eduar and Högqvist Tabor, Vedrana and Hydbring, Per and Grandien, Alf and Alzrigat, Mohammad and Larsson, Lars-Gunnar}},
issn = {{1551-4005}},
language = {{eng}},
number = {{1}},
pages = {{23--38}},
publisher = {{Landes Bioscience}},
series = {{Cell Cycle}},
title = {{Pharmacological inactivation of CDK2 inhibits MYC/BCL-XL-driven leukemia in vivo through induction of cellular senescence}},
url = {{http://dx.doi.org/10.1080/15384101.2020.1855740}},
doi = {{10.1080/15384101.2020.1855740}},
volume = {{20}},
year = {{2021}},
}