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 nonintensive acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) treatment, also by virtue of their activity in patients with adverse genetics, for example, monosomal karyotypes, often with losses on chromosome 7, 5, or 17. No comparable activity is observed with cytarabine, 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 HMAs decitabine and azacitidine. An unbiased RNA-sequencing approach was developed to interrogate decitabine-induced transcriptome changes in AML cell lines with or without a deletion of chromosomes 7q, 5q or 17p. HMA treatment 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. Decitabine 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 decitabine treatment in vivo in serially sorted peripheral blood AML blasts. In patient-derived monosomal karyotype AML murine xenografts, decitabine treatment resulted in superior survival rates compared with cytarabine. 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 cytarabine in this difficult-to-treat patient group. Significance: These findings unravel the molecular mechanism underlying the intriguing clinical activity of HMAs in AML/MDS patients with chromosome 7 deletions and other monosomal karyotypes. See related commentary by O'Hagan et al., p. 813

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia

“…Decitabine reactivated multiple transposable elements, such as double-strand RNA sensor RIG-I and interferon regulatory factor 7. Similar changes were observed in experiments on peripheral blood blasts from patients with AML receiving in vivo treatment with decitabine [44].…”

Losing DNA methylation at repetitive elements and breaking bad

“…Although more research is needed to better determine types of actions elicited by DNAh in different REs for a protective or toxic effect in the brain, current achievements are promising to predict how these different activities can be counterbalanced. In this regard, recent studies have highlighted the emerging role in immuno-oncology of the reactivation of TEs by the therapeutic administration of demethylating agents as decitabine [ 221 – 223 ]. Demethylating drugs, in fact, have been used for almost two decades in cancer treatment [ 224 ] In addition to this role, demethylating agents, through reactivation of TEs, have been more recently described as inducers of innate immunity [ 221 , 225 ] and promoters of the immunosurveillance by enhancing antiviral signalling and the production of neoantigens in tumour cells [ 222 , 223 ].…”

Hypomethylating agents (HMA) for the treatment of acute myeloid leukemia and myelodysplastic syndromes: mechanisms of resistance and novel HMA-based therapies

“…The modulating role of bi-allelic vs. single TP53 lesions as predictors of response to HMA treatment and outcome after allografting is the subject of ongoing studies. Also under study are mechanistic aspects of the (albeit transient) response to HMA in these adverse-genetics AML, whether by an interaction of mutated p53 protein with HMA, or by their gene-reactivating effects being particularly attracted by monosomic chromosomes (e.g., chromosome 7) presenting broad epigenetic silencing [27].…”