Decitabine Induces Gene Derepression on Monosomic Chromosomes: <i>In Vitro</i> and <i>In Vivo</i> Effects in Adverse-Risk Cytogenetics AML

Abstract Hypomethylating agents (HMA) have become the backbone of nonintensive acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) treatment, also by virtue their activity in patients with adverse genetics, for example, monosomal karyotypes, often losses on chromosome 7, 5, or 17. No comparable is observed cytarabine, a cytidine analogue without DNA-hypomethylating properties. As evidence exists compounding hypermethylation and gene silencing hemizygous tumor suppressor genes (TSG), we thus hypothesized that this effect may preferentially be reversed HMAs decitabine azacitidine. An unbiased RNA-sequencing approach was developed to interrogate decitabine-induced transcriptome changes AML cell lines deletion chromosomes 7q, 5q 17p. HMA treatment upregulated several TSG genomic region, significantly derepressing endogenous retrovirus (ERV)3–1, promoter demethylation, enhanced chromatin accessibility, increased H3K4me3 levels. Decitabine globally reactivated multiple transposable elements, activation dsRNA sensor RIG-I interferon regulatory factor (IRF)7. Induction ERV3–1 mRNA during vivo serially sorted peripheral blood blasts. In patient-derived karyotype murine xenografts, resulted superior survival rates compared cytarabine. Collectively, these data demonstrate preferential derepression ERV reactivation chromosomal deletions, providing mechanistic explanation supports clinical observation superiority over cytarabine difficult-to-treat patient group. Significance: These findings unravel molecular mechanism underlying intriguing AML/MDS 7 deletions other karyotypes. See related commentary O'Hagan et al., p. 813