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Low-input proteomics identifies vWF as a negative regulator of Tet2 mutant hematopoietic stem cell expansion

Jassinskaja, Maria LU ; Bode, Daniel ; Gonka, Monika ; Roumeliotis, Theodoros I. ; Hogg, Alexander J. ; Rubio Lara, Juan A. ; Bennett, Ellie ; Milek, Joanna ; Elberfeld, Samuel and Theeuwes, Bart , et al. (2026) In Cell Reports 45(1).
Abstract

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-/-) 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-/- HSCs than transcriptomic approaches and identify extracellular... (More)

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-/-) 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-/- 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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
biophysics, CP: stem cell research, extracellular matrix, hematopoietic stem cell, multi-omics, physical biology, proteomics, self-renewal, single cell biology, TET2
in
Cell Reports
volume
45
issue
1
article number
116770
publisher
Cell Press
external identifiers
  • pmid:41447537
  • scopus:105029029572
ISSN
2211-1247
DOI
10.1016/j.celrep.2025.116770
language
English
LU publication?
yes
id
5be30f85-19bf-4c9c-bbeb-3f06f59d723b
date added to LUP
2026-02-19 13:48:06
date last changed
2026-02-20 03:00:02
@article{5be30f85-19bf-4c9c-bbeb-3f06f59d723b,
  abstract     = {{<p>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-/-) 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-/- 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.</p>}},
  author       = {{Jassinskaja, Maria and Bode, Daniel and Gonka, Monika and Roumeliotis, Theodoros I. and Hogg, Alexander J. and Rubio Lara, Juan A. and Bennett, Ellie and Milek, Joanna and Elberfeld, Samuel and Theeuwes, Bart and Vijayabaskar, M. S. and Cosme, Lilia Cabrera and Chi Che, James Lok and MacDonald, Sandy and Ahmed, Sophia and Hall, Benjamin A. and Vasey, Grace and Kooi, Helena and Belmonte, Miriam and Shepherd, Mairi S. and Brackenbury, William J. and Kucinski, Iwo and Yamazaki, Satoshi and Holding, Andrew N. and Cull, Alyssa H. and Wilson, Nicola K. and Göttgens, Berthold and Choudhary, Jyoti and Kent, David G.}},
  issn         = {{2211-1247}},
  keywords     = {{biophysics; CP: stem cell research; extracellular matrix; hematopoietic stem cell; multi-omics; physical biology; proteomics; self-renewal; single cell biology; TET2}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Cell Press}},
  series       = {{Cell Reports}},
  title        = {{Low-input proteomics identifies vWF as a negative regulator of Tet2 mutant hematopoietic stem cell expansion}},
  url          = {{http://dx.doi.org/10.1016/j.celrep.2025.116770}},
  doi          = {{10.1016/j.celrep.2025.116770}},
  volume       = {{45}},
  year         = {{2026}},
}