Fig. 1

The roles of Tet proteins in normal and disease hematopoiesis as demonstrated by genetically-modified mouse models. Knockout mouse studies suggested that Tet2 regulates the dynamic differentiation and lineage commitment of HSPCs at multiple differentiation stages, including HSC-to-MPP differentiation, MPP-to-CLP, CMP-MEP, and CMP-GMP lineage commitments, pro-B-to-pre-B transition, GC B to plasma cells (PCs) vs. B1 B-cell lineage commitment, CD4 naïve T-to-Treg vs. Th17 and iNKT-to-NKT1 vs. NKT17 lineage decision, as well as CD8⁺ memory T cell generation. This explains the pleiotropic hematopoietic disease profile of TET2^MT malignancies. Tet1 antagonizes Tet2 activity in the regulation of HSC self-renewal and myeloid vs. B-cell lineage commitment. However, Tet1 collaborates with Tet2 in regulating immature B-cell-to-mature B-cell differentiation and naïve CD4⁺ T-to-Treg cell differentiation. Consequently, knockout of both Tet1 and Tet2 in HSPCs leads to B-ALL-like disease owing to the aberrant expansion of immature B-cells, while knockout of both Tet1 and Tet2 in CD4⁺ T or Treg cells, resulting in autoimmune/inflammatory disease due to impaired Treg cell production. However, Tet3 compensates for Tet2 activity in almost all types of cells studied. As a result, mice with Tet2 and Tet3 compound-deletion in 1) HSPCs develop AML within 1–3 months; 2) pro-B cells develop B-ALL within months; 3) immature B-cells develop lupus-like autoimmune diseases; 4) CD4⁺ T-cells develop PTCL with NKT17 phenotype, and 5) FoxP3⁺ Treg cells develop autoimmune lymphadenopathy. The TFs in red font are lineage-specific pioneer TFs that are required for recruiting Tet proteins to DNA for DNA demethylation, while the TFs in blue font are dependent on Tet2-mediated demethylation to access their target gene enhancers. The TFs in black font are dependent on Tet2 for their expression. (Created with BioRender.com)