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Selection of pre-leukemic hematopoietic stem cells driven by distinct extracellular matrix molecules

ABSTRACT: Despite rapid advances in mapping genetic drivers and gene expression changes in hematopoietic stem cells (HSCs), there is a relative paucity of studies at the protein level. Here, we perform a deep, multi-omic characterization (epigenome, transcriptome and proteome) of HSCs carrying a loss-of-function mutation in Tet2, a key driver of increased self-renewal in blood cancers. Using state-of-the-art, multiplexed, low-input mass spectrometry (MS)-based proteomics, we profile wildtype (WT) and TET2-deficient (Tet2-/-) HSCs and show that the proteome captures previously unrecognized molecular processes which define the pre-leukemic HSC molecular landscape. Specifically, we obtain more accurate stratification of WT and Tet2-/- HSCs than transcriptomic approaches and identify extracellular matrix (ECM) molecules as novel points of dysregulation 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.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Graeme Benstead-Hume

LAB HEAD: Jyoti Choudhary

PROVIDER: PXD059814 | Pride | 2025-11-13

REPOSITORIES: Pride

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			Action	DRS
	20180523_DB_Cambridge_20k_TMT_LMS.msf	Msf
	20180523_DB_Cambridge_20k_TMT_LMS.msfView	Msf
	20180523_DB_Cambridge_20k_TMT_LMS.pdResult	Other
	20180523_DB_Cambridge_20k_TMT_LMS.pdResultView	Other
	20180523_DB_Cambridge_20k_TMT_LMS.pdStudy	Other

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