CCND3 is indispensable for the maintenance of B-cell acute lymphoblastic leukemia.


Journal

Oncogenesis
ISSN: 2157-9024
Titre abrégé: Oncogenesis
Pays: United States
ID NLM: 101580004

Informations de publication

Date de publication:
10 Jan 2022
Historique:
received: 06 07 2021
accepted: 22 12 2021
revised: 08 12 2021
entrez: 11 1 2022
pubmed: 12 1 2022
medline: 12 1 2022
Statut: epublish

Résumé

The D-type cyclins (CCND1, CCND2, and CCND3) in association with CDK4/6 are known drivers of cell cycle progression. We reported previously that inactivation of FOXO1 confers growth arrest and apoptosis in B-ALL, partially mediated by subsequent depletion of CCND3. Given that previously the canonical MYC target CCND2 has been considered to play the major role in B-ALL proliferation, further investigation of the role of FOXO1 in CCND3 transcription and the role of CCND3 in B-ALL is warranted. In this study, we demonstrated that CCND3 is essential for the proliferation and survival of B-ALL, independent of the mutational background. Respectively, its expression at mRNA level exceeds that of CCND1 and CCND2. Furthermore, we identified FOXO1 as a CCND3-activating transcription factor in B-ALL. By comparing the effects of CCND3 depletion and CDK4/6 inhibition by palbociclib on B-ALL cells harboring different driver mutations, we found that the anti-apoptotic effect of CCND3 is independent of the kinase activity of the CCND3-CDK4/6 complex. Moreover, we found that CCND3 contributes to CDK8 transcription, which in part might explain the anti-apoptotic effect of CCND3. Finally, we found that increased CCND3 expression is associated with the development of resistance to palbociclib. We conclude that CCND3 plays an essential role in the maintenance of B-ALL, regardless of the underlying driver mutation. Moreover, downregulation of CCND3 expression might be superior to inhibition of CDK4/6 kinase activity in terms of B-ALL treatment.

Identifiants

pubmed: 35013097
doi: 10.1038/s41389-021-00377-0
pii: 10.1038/s41389-021-00377-0
pmc: PMC8748974
doi:

Types de publication

Journal Article

Langues

eng

Pagination

1

Subventions

Organisme : NIAID NIH HHS
ID : R01 AI164692
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA157644
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA213138
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197628
Pays : United States

Informations de copyright

© 2022. The Author(s).

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Auteurs

Franz Ketzer (F)

Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany.

Hend Abdelrasoul (H)

Institute of Immunology, Ulm University Medical Center, Albert-Einstein-Allee 11, 89081, Ulm, Germany.

Mona Vogel (M)

Institute of Molecular Medicine, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany.

Ralf Marienfeld (R)

Institute of Pathology, Ulm University Medical Center, Albert-Einstein-Allee 11, 89081, Ulm, Germany.

Markus Müschen (M)

Center of Molecular and Cellular Oncology, Yale School of Medicine, 300 George Street, 06520, New Haven, CT, USA.

Hassan Jumaa (H)

Institute of Immunology, Ulm University Medical Center, Albert-Einstein-Allee 11, 89081, Ulm, Germany.

Thomas Wirth (T)

Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany. thomas.wirth@uni-ulm.de.

Alexey Ushmorov (A)

Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany. alexey.ushmorov@uni-ulm.de.

Classifications MeSH