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Review
. 2022 Oct 7;41(1):294.
doi: 10.1186/s13046-022-02496-x.

Role of TET dioxygenases in the regulation of both normal and pathological hematopoiesis

Kanak Joshi #  1 , Lei Zhang #  1   2 , Peter Breslin S J  1   3 , Ameet R Kini  4 , Jiwang Zhang  5   6
Affiliations
Review

Role of TET dioxygenases in the regulation of both normal and pathological hematopoiesis

Kanak Joshi et al. J Exp Clin Cancer Res. .

Abstract

The family of ten-eleven translocation dioxygenases (TETs) consists of TET1, TET2, and TET3. Although all TETs are expressed in hematopoietic tissues, only TET2 is commonly found to be mutated in age-related clonal hematopoiesis and hematopoietic malignancies. TET2 mutation causes abnormal epigenetic landscape changes and results in multiple stages of lineage commitment/differentiation defects as well as genetic instability in hematopoietic stem/progenitor cells (HSPCs). TET2 mutations are founder mutations (first hits) in approximately 40-50% of cases of TET2-mutant (TET2MT) hematopoietic malignancies and are later hits in the remaining cases. In both situations, TET2MT collaborates with co-occurring mutations to promote malignant transformation. In TET2MT tumor cells, TET1 and TET3 partially compensate for TET2 activity and contribute to the pathogenesis of TET2MT hematopoietic malignancies. Here we summarize the most recent research on TETs in regulating of both normal and pathogenic hematopoiesis. We review the concomitant mutations and aberrant signals in TET2MT malignancies. We also discuss the molecular mechanisms by which concomitant mutations and aberrant signals determine lineage commitment in HSPCs and the identity of hematopoietic malignancies. Finally, we discuss potential strategies to treat TET2MT hematopoietic malignancies, including reverting the methylation state of TET2 target genes and targeting the concomitant mutations and aberrant signals.

Keywords: Concurring mutations; Differentiation; HSPCs; Leukemia; MDS; Self-renewal; TET2.

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Conflict of interest statement

The authors declare that they have no competing financial or professional interests.

Figures

Fig. 1
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 TET2MT 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)
Fig. 2
Fig. 2
The roles of TETs in the pathogenesis of human hematopoietic malignancies. Studies of human hematopoietic malignancies suggested that TET2 is a tumor suppressor for almost all types of hematopoietic malignancies, while TET1 is a tumor suppressor for B-cell malignancies but a tumor promotor for myeloid or T-cell malignancies. TET3 is required for the survival and proliferation of myeloid malignancies. However, its role in T- and B-cell malignancies has yet to be determined. (Created with BioRender.com)
Fig. 3
Fig. 3
Concurrent genetic mutations of TET2MT human myeloid malignancies. A. Mutations of ASXL1, SRSF2, DNMT3A, and EZH2 concur in all types of myeloid malignancies. Second allele mutations of TET2 are commonly detected in MDS and MPNs but not in de novo AML. In addition, mutations in splicing factors such as SF3B1 and U2AF1 are commonly detected in MDS, while mutations of signaling molecules are commonly detected in MPN and AML patients. B Idh1/2 regulate the production of α-KG and promote TET2 activity, whereas mutant Idh1/2 regulate the production of 2HG and repress TET2 activity. TET2 regulates the differentiation of myeloid progenitors primarily by interacting with WT1 for DNA binding. Mutations of Idh1/2 and WT1 are exclusive in TET2MT myeloid malignancies. (Created with BioRender.com)
Fig. 4
Fig. 4
Concurrent genetic mutations of TET2MT PTCL. A. RHOAG17V mutation and mutations of key components of TCR and ICOS signaling pathways such as CD28, PLCG1, and VAV1 commonly co-occur in TETMT PTCL. Consequently, TCR and ICOS signaling are activated in TET2MT PTCL, determining the Tfh phenotype. In addition, second TET2 mutations are commonly detected in TET2MT PTCL. Moreover, IDH2R172K mutation also commonly co-occurs in TET2MT PTCL. B. The molecular mechanism of RHOAG17V mutation in the pathogenesis of PTCL in collaboration with TET2MT. RHOAG17V mutation antagonizes the normal function of RHOA and activates ICOS-AKT-mTOR and PLCγ1-NFAT signaling by stimulating the activation of VAV1. TET2MT collaborates with RHOAG17V mutation in the regulation of FoxO1 activity in T-cells. (Created with BioRender.com)
Fig. 5
Fig. 5
Oncogenic collaboration of mutations with TET2MT in animal models. Tet2MT mice develop MPNs, AITL-like, AML-like, or T-ALL-like diseases when combined with Dnmt3AR882H mutation or Dnmt3A deletion, and accelerated MPN or AML when combined with N-rasG12D mutation. However, Tet2MT mice develop AITL, AML, MPN, MDS/MPN, or mastocytosis when combined with RhoAG17V, Flt3ITD/AML1-ETO/NcstnMT, Jak2V617F, Ezh2MT/Asxl1MT/BcorMT or KitD816V, respectively. All these mutant phenotypes resemble the disease phenotypes of patients having the same combinations of mutations. (Created with BioRender.com)
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