Peer-reviewedCC BYNature communications
Ablation of CDK6 and STAT5B rewires T cell developmental dynamics and prevents ALK⁺ lymphoma formation.
14 affiliations
- 1Department of Biological Sciences and Pathobiology, Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
- 2Department of Internal Medicine I (Oncology, Hematology, Clinical Immunology, and Rheumatology), Saarland University Medical School, Homburg, Germany.
- 3Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
- 4Department of Experimental Medicine, University of Genoa, Genoa, Italy.
- 5Department of Biological Sciences and Pathobiology, Unit of Pathology, University of Veterinary Medicine, Vienna, Austria.
- 6Department of Pathology, Medical University of Vienna, Vienna, Austria.
- 7Christian Doppler Laboratory for Applied Metabolomics, Medical University of Vienna, Vienna, Austria.
- 8Center for Biomarker Research in Medicine, CBmed GmbH, Graz, Austria.
- 9Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
- 10Department of Molecular Biology, Umeå University, Umeå, Sweden.
- 11Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, Salzburg, Austria.
- 12University of Innsbruck, Innsbruck, Austria.
- 13Department of Biological Sciences and Pathobiology, Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria. [email protected].
- 14Department of Biological Sciences and Pathobiology, Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria. [email protected].
Abstract
CDK6 and STAT5B are well-established oncogenic drivers, but their interplay during transformation remains poorly understood. Here, we demonstrate that simultaneous genetic deletion of Cdk6 and Stat5b in an NPM-ALKTg/+ mouse model completely prevents tumor formation. Immature DN2/3 thymocytes are identified as the cellular origin of ALK-driven malignancy. Single-cell transcriptomics reveals a tumor-specific differentiation trajectory that is fully disrupted by combined Cdk6/Stat5b loss, coinciding with a developmental shift. We uncover shared transcriptional targets of CDK6 and STAT5B involved in cell-cycle regulation and apoptosis at the tumor initiation stage. In human ALCL cells, dual deletion of CDK6 and STAT5B induces context-dependent synthetic lethality, exposing a potential therapeutic vulnerability. A transcriptional signature derived from CDK6/STAT5B-dependent tumor initiation genes identifies a high-risk subgroup of ALCL patients with worse survival. Together, these findings establish a molecular link between thymocyte development, the crosstalk of CDK6 and STAT5B, oncogenic signaling, and clinical outcome in ALCL.
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BibTeX
@article{kendler2026ablation,
title = {{Ablation of CDK6 and STAT5B rewires T cell developmental dynamics and prevents ALK⁺ lymphoma formation.}},
author = {Jonatan Kendler and Maximilian Sexl and Alessia Schirripa and Elisabeth Gamper and Hager El Kersh and Barbara Maurer and Reinhard Grausenburger and Klavdija Krause and Dua Shahid and Alexander Pichler and Giorgia Damonte and Tania Brandstoetter and Michaela Prchal-Murphy and Stefania Massari and Sabine Lagger and Lukas Kenner and Richard Moriggl and Philipp B Staber and Veronika Sexl and Sebastian Kollmann and Karoline Kollmann and Thorsten Klampfl},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77466-4},
url = {https://europepmc.org/article/MED/42881166},
note = {CC BY},
}
RIS
TY - JOUR
TI - Ablation of CDK6 and STAT5B rewires T cell developmental dynamics and prevents ALK⁺ lymphoma formation.
AU - Jonatan Kendler
AU - Maximilian Sexl
AU - Alessia Schirripa
AU - Elisabeth Gamper
AU - Hager El Kersh
AU - Barbara Maurer
AU - Reinhard Grausenburger
AU - Klavdija Krause
AU - Dua Shahid
AU - Alexander Pichler
AU - Giorgia Damonte
AU - Tania Brandstoetter
AU - Michaela Prchal-Murphy
AU - Stefania Massari
AU - Sabine Lagger
AU - Lukas Kenner
AU - Richard Moriggl
AU - Philipp B Staber
AU - Veronika Sexl
AU - Sebastian Kollmann
AU - Karoline Kollmann
AU - Thorsten Klampfl
PY - 2026
DA - 2026/09/15
JO - Nature communications
DO - 10.1038/s41467-026-77466-4
UR - https://europepmc.org/article/MED/42881166
AB - CDK6 and STAT5B are well-established oncogenic drivers, but their interplay during transformation remains poorly understood. Here, we demonstrate that simultaneous genetic deletion of Cdk6 and Stat5b in an NPM-ALKTg/+ mouse model completely prevents tumor formation. Immature DN2/3 thymocytes are identified as the cellular origin of ALK-driven malignancy. Single-cell transcriptomics reveals a tumor-specific differentiation trajectory that is fully disrupted by combined Cdk6/Stat5b loss, coinciding with a developmental shift. We uncover shared transcriptional targets of CDK6 and STAT5B involved in cell-cycle regulation and apoptosis at the tumor initiation stage. In human ALCL cells, dual deletion of CDK6 and STAT5B induces context-dependent synthetic lethality, exposing a potential therapeutic vulnerability. A transcriptional signature derived from CDK6/STAT5B-dependent tumor initiation genes identifies a high-risk subgroup of ALCL patients with worse survival. Together, these findings establish a molecular link between thymocyte development, the crosstalk of CDK6 and STAT5B, oncogenic signaling, and clinical outcome in ALCL.
SN - 2041-1723
ER -