Low-input proteomics identifies vWF as a negative regulator of Tet2 mutant hematopoietic stem cell expansion
Despite rapid advances in mapping genetic drivers and gene expression changes in hematopoietic stem cells (HSCs), few studies exist at the protein level. We perform a deep, multi-omics characterization (epigenome, transcriptome, and proteome) of HSCs in a mouse model carrying a loss-of-function mutation in Tet2, a driver of increased self-renewal in blood cancers. Using state-of-the-art, multiplexed, low-input mass spectrometry (MS)-based proteomics, we profile TET2-deficient (Tet2<sup>-/-</sup>) HSCs, revealing previously unrecognized molecular processes that define the pre-leukemic HSC molecular landscape. Specifically, we obtain more accurate stratification of wild-type and Tet2<sup>-/-</sup> HSCs than transcriptomic approaches and identify extracellular matrix (ECM) molecules as being dysregulated upon TET2 loss. HSC expansion assays using ECM-functionalized hydrogels confirm a selective effect on the expansion of Tet2-mutant HSCs. Taken together, our study represents a comprehensive molecular characterization of Tet2-mutant HSCs and identifies a previously unanticipated role of ECM molecules in regulating self-renewal of disease-driving HSCs.
Authors
- Sandy MacDonald (ORCID: https://orcid.org/0000-0002-4112-0987)
- Alyssa Cull (ORCID: https://orcid.org/0000-0003-1855-8849)
- Berthold Göttgens (ORCID: https://orcid.org/0000-0001-6302-5705)
- Maria Jassinskaja (ORCID: https://orcid.org/0000-0003-1493-8510)
- William J. Brackenbury (ORCID: https://orcid.org/0000-0001-6882-3351)
- Benjamin A. Hall (ORCID: https://orcid.org/0000-0003-0355-2946)
- Andrew N. Holding (ORCID: https://orcid.org/0000-0002-8459-7048)
- Bart Theeuwes (ORCID: https://orcid.org/0000-0003-3089-4773)
- Daniel Bode (ORCID: https://orcid.org/0000-0003-4415-7387)
- Monika Gońka (ORCID: https://orcid.org/0000-0002-8487-3364)
- Lilia Cabrera Cosme
- Miriam Belmonte
- Alexander Hogg
- Mairi Shepherd (ORCID: https://orcid.org/0000-0002-4328-9882)
- Nicola K. Wilson (ORCID: https://orcid.org/0000-0003-0865-7333)
- Joanna Milek
- Grace Vasey
- Ellie Bennett (ORCID: https://orcid.org/0009-0004-5889-0306)
- Sophia Ahmed
- L C James (ORCID: https://orcid.org/0000-0003-4621-8649)
- Jari Laru (ORCID: https://orcid.org/0000-0003-0347-0182)
- Helena Kooi
- Samuel Elberfeld
- David G. Kent
- Theodoros I. Roumeliotis
- Jyoti Choudhary
- Satoshi Yamazaki
- Iwo Kucinski
- M.S. Vijayabaskar
Institutions
- Institute of Cancer Research (GB)
- Lund University (SE)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University College London (GB)
- University of York (GB)
- The University of Tokyo (JP)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-12-24
- DOI
- https://doi.org/10.1016/j.celrep.2025.116770
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00