Summary
The molecular complexity of the bone marrow (BM) microenvironment and its
response to stress are incompletely understood, despite its key role in the
regulation of hematopoiesis. Here we map the transcriptional landscape of BM
vascular, perivascular, and osteoblast niche populations at single-cell
resolution at both homeostasis and under stress hematopoiesis. This analysis
revealed a previously unappreciated level of cellular heterogeneity within the
BM niche, identified novel cellular subsets, and resolved cellular sources of
pro-hematopoietic growth factors, chemokines, and membrane-bound ligands. Under
conditions of stress, our studies revealed a significant transcriptional
remodeling of these niche elements, including an adipocytic skewing of the
perivascular cells. Among the stress-induced changes, we observed that vascular
Notch ligand delta-like ligands (Dll1,4) were downregulated. In
the absence of vascular Dll4, hematopoietic stem cells (HSC)
prematurely induced a myeloid transcriptional program. These findings refine our
understanding of the cellular architecture of the BM niche, reveal a dynamic and
heterogeneous molecular landscape that is highly sensitive to stress, and
illustrate the utility of single cell transcriptomic data in systematically
evaluating the regulation of hematopoiesis by discrete niche populations.
SUMMARY
Loss-of-function mutations in TET2 occur frequently in patients with clonal hematopoiesis, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) and are associated with a DNA hypermethylation phenotype. To determine the role of TET2 deficiency in leukemia stem cell maintenance, we generated a reversible transgenic RNAi mouse to model restoration of endogenous Tet2 expression. Tet2 restoration reverses aberrant hematopoietic stem and progenitor cell (HSPC) self-renewal in vitro and in vivo. Treatment with vitamin C, a cofactor of Fe2+ and α-KG-dependent dioxygenases, mimics TET2 restoration by enhancing 5-hydroxymethylcytosine formation in Tet2-deficient mouse HSPCs and suppresses human leukemic colony formation and leukemia progression of primary human leukemia PDXs. Vitamin C also drives DNA hypomethylation and expression of a TET2-dependent gene signature in human leukemia cell lines. Furthermore, TET-mediated DNA oxidation induced by vitamin C treatment in leukemia cells enhances their sensitivity to PARP inhibition and could provide a safe and effective combination strategy to selectively target TET deficiency in cancer.
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