The DNA methyltransferase inhibitor 5-aza-4'-thio-2'-deoxycytidine induces C>G transversions and acute lymphoid leukemia development.
Ryan M BertoliYang Jo ChungMichael J DifilippantonioAnthony WokaschMadison R B MarascoHaley L KlimaszewskiSusannah GammellYuelin Jack ZhuRobert L WalkerDengchao CaoAjay KhannaMatthew J WalterJames H DoroshowPaul S MeltzerPeter D AplanPublished in: Cancer research (2024)
DNA methyltransferase inhibitors (DNMTi), most commonly cytidine analogs, are compounds that decrease 5'-cytosine methylation. DNMTi are used clinically based on the hypothesis that cytosine demethylation will lead to re-expression of tumor suppressor genes. 5-Aza-4'-thio-2'-deoxycytidine (Aza TdCyd or ATC) is a recently described thiol substituted DNMTi that has been shown to have anti-tumor activity in solid tumor models. Here, we investigated the therapeutic potential of ATC in a murine transplantation model of myelodysplastic syndrome. ATC treatment led to transformation of transplanted wild-type bone marrow nucleated cells into lymphoid leukemia, and healthy mice treated with ATC also developed lymphoid leukemia. Whole exome sequencing revealed thousands of acquired mutations, almost all of which were C>G transversions in a specific 5'-NCG-3' context. These mutations involved dozens of genes involved in human lymphoid leukemia, such as Notch1, Pten, Pax5, Trp53, and Nf1. Human cells treated in vitro with ATC showed thousands of acquired C>G transversions in a similar context. Deletion of Dck, the rate-limiting enzyme for the cytidine salvage pathway, eliminated C>G transversions. Taken together, these findings demonstrate a highly penetrant mutagenic and leukemogenic phenotype associated with ATC.
Keyphrases
- bone marrow
- acute myeloid leukemia
- wild type
- mesenchymal stem cells
- circulating tumor
- endothelial cells
- cell proliferation
- genome wide
- cell free
- poor prognosis
- pi k akt
- single molecule
- induced apoptosis
- molecular docking
- signaling pathway
- dna methylation
- liver failure
- stem cells
- cell cycle arrest
- oxidative stress
- nuclear factor
- single cell
- type diabetes
- immune response
- atomic force microscopy
- adipose tissue
- lps induced
- newly diagnosed
- cell death
- inflammatory response
- endoplasmic reticulum stress
- respiratory failure
- long non coding rna
- transcription factor
- aortic dissection
- skeletal muscle
- nucleic acid
- acute respiratory distress syndrome
- molecular dynamics simulations
- insulin resistance
- high speed