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New Paper "Decitabine induces gene derepression on monosomic chromosomes: in vitro and in vivo effects in adverse-risk cytogenetics AML"

Abstract - Hypomethylating agents (HMA) have become the backbone of non-intensive AML/MDS treatment, primarily by virtue of their activity in patients with adverse genetics, e.g., monosomal karyotypes, often with losses on chromosome 7, 5 or 17.

However, no comparable activity is observed with cytarabine (AraC), a cytidine analogue without DNA-hypomethylating properties. As evidence exists for compounding hypermethylation and gene silencing of hemizygous tumor suppressor genes (TSG), we thus hypothesized that this effect may preferentially be reversed by the HMA decitabine (DAC) and azacitidine (AZA).

An unbiased RNA-seq approach was developed to interrogate DAC-induced transcriptome changes in AML cell lines with or without a deletion of chromosomes 7q, 5q or 17p. HMA treatment (DAC or AZA) preferentially upregulated several hemizygous TSG in this genomic region, significantly derepressing endogenous retrovirus (ERV)3-1 with promoter demethylation, enhanced chromatin accessibility, and increased H3K4me3 levels. DAC globally reactivated multiple transposable elements, with activation of the dsRNA sensor RIG-I and interferon regulatory factor (IRF)7. Induction of ERV3-1 and RIG-I mRNA was also observed during DAC treatment in vivo in serially sorted peripheral blood AML blasts. In patient-derived murine monosomal karyotype AML xenografts, DAC treatment resulted in superior survival rates compared to AraC. Collectively, these data demonstrate preferential gene derepression and ERV reactivation in AML with chromosomal deletions, providing a mechanistic explanation that supports the clinical observation of superiority of HMA over AraC in this difficult-to-treat patient group.