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. 2022 Oct 4;12(10):141.
doi: 10.1038/s41408-022-00739-w.

TET2 deficiency promotes MDS-associated leukemogenesis

Feiteng Huang  1   2 , Jie Sun  1 , Wei Chen  3 , Lei Zhang  1 , Xin He  1 , Haojie Dong  1 , Yuhui Wu  1 , Hanying Wang  1 , Zheng Li  1 , Brian Ball  4 , Samer Khaled  4 , Guido Marcucci  1   4 , Ling Li  5
Affiliations

TET2 deficiency promotes MDS-associated leukemogenesis

Feiteng Huang et al. Blood Cancer J. .

Erratum in

No abstract available

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Tet2 deficiency expands the stem/progenitor pool and accelerates leukemia transformation in a murine model of MDS.
A Survival of NHD13/Tet2-WT (n = 20; median survival, 347 days) and NHD13/Tet2-KO (n = 16; median survival, 199 days) mice. B WBC count of WT, Tet2-KO, NHD13, and NHD13/Tet2-KO mice (30-weeks-old). C Frequencies of BM c-kit+ cells from indicated mice at 30-weeks-old. D Wright–Giemsa staining of BM cells from indicated mice. Green arrows: dysplastic cells; red arrows: blast cells; scale bars, 20 μm. E Total cell number and percentage of LK subsets in BM of indicated primary mice at a pre-leukemic stage (20-weeks-old). F Apoptosis of LK population in the BM of indicated mice based on Annexin V staining. G Lethally-irradiated mice were transplanted with 2 × 105 LK cells from pre-leukemic NHD13/Tet2-WT (n = 10) or NHD13/Tet2-KO (n = 18) mice plus 2 × 105 unfractionated WT support cells. Shown is chimerism of donor-derived cells (CD45.2+) in PB of recipient mice at different time points. *P < 0.05; **P < 0.01; ***P < 0.001, ****P < 0.0001.
Fig. 2
Fig. 2. Vitamin C treatment mimics Tet2 restoration and blocks leukemogenesis.
A Depicted are 37 genes identified from PRECOG based on two conditions (VAF > 50%, mutation ratio >0.5). Red dots represent preferential enrichment of mutations associated with AML poor prognosis. B c-kit+ BM cells from NHD13 mice were transduced with shRNA targeting indicated genes and then plated for CFC. Shown are colony number (left) and cell number (right) of shArih2 or shCtrl cells after first plating. C Overall survival of total MDS patients, stratified by ARIH2 expression levels. D 5hmC peaks around mutation sites (±1 kb) were counted in Tet2-WT or Tet2-KO NHD13 mice (P = 0.0265, paired t test). E Representative University of California Santa Cruz (UCSC) tracks showing 5hmC peaks (red boxes) associated with Arih2 (Chr9: 108607200–108607400) and Mtss1 (Chr15: 58979400–58979800) loci. Tracks showing 5hmC enrichment were from biological replicates of BM c-kit+ cells from NHD13/Tet2-WT (N) or NHD13/Tet2-KO (NT) mice. F Vitamin C treatment of mice reconstituted with NHD13/Tet2fl/fl and NHD13/Tet2fl/fl/Mx1-Cre BM. Tet2 was deleted by injection of poly(I:C) at 6 weeks post-transplant. Mice were intraperitoneally injected with normal saline (vehicle) or ascorbate (ASC, 4 g/kg), 5 days a week for 16 weeks. WBC counts were monitored at 24 weeks post-transplant. G NHD13/Tet2fl/fl, NHD13/Tet2-/-, and NHD13/Tet2-/-/shTet3 BM c-kit+ cells were treated with vehicle or ASC (0.25 mM) for 3 days and relative 5hmC levels in total DNA were measured by ELISA. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.
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References

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