Ablation of CDK6 and STAT5B rewires T cell developmental dynamics and prevents ALK+ lymphoma formation
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-ALK Tg/+ 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.
Authors
- Tania Brandstoetter (ORCID: https://orcid.org/0000-0003-4037-5352)
- Richard Moriggl (ORCID: https://orcid.org/0000-0003-0918-9463)
- Alessia Schirripa (ORCID: https://orcid.org/0000-0001-5446-9136)
- Jonatan Kendler (ORCID: https://orcid.org/0000-0002-2470-4868)
- Karoline Kollmann (ORCID: https://orcid.org/0000-0002-7937-4245)
- Elisabeth Gamper
- Klavdija Bastl (ORCID: https://orcid.org/0000-0002-8383-1330)
- Lukas Kenner (ORCID: https://orcid.org/0000-0003-2184-1338)
- Thorsten Klampfl (ORCID: https://orcid.org/0000-0002-6666-9773)
- Reinhard Grausenburger
- A. G. Pichler
- Michaela Prchal‐Murphy
- Veronika Sexl (ORCID: https://orcid.org/0000-0001-9363-0412)
- Barbara Maurer (ORCID: https://orcid.org/0000-0003-1343-8194)
- Sebastian Kollmann (ORCID: https://orcid.org/0000-0001-7911-9896)
- Sabine Lagger (ORCID: https://orcid.org/0000-0002-3032-9910)
- Dua Shahid
- Maximilian Sexl
- Giorgia Damonte
- Philipp B. Staber
- Stefania Massari
- Hager El Kersh (ORCID: https://orcid.org/0009-0006-5312-6039)
Institutions
- University of Veterinary Medicine Vienna (AT)
- University of Salzburg (AT)
- Universität Innsbruck (AT)
- Comprehensive Cancer Center Vienna (AT)
- Medical University of Vienna (AT)
- University of Genoa (IT)
- Saarland University (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-09-15
- DOI
- https://doi.org/10.1038/s41467-026-77466-4
- Primary Topic
- Lymphoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Österreichischen Akademie der Wissenschaften
- Austrian Science Fund
- Veterinärmedizinische Universität Wien