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

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...

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Published in:	Cancer research (Chicago, Ill.) Vol. 81; no. 4; pp. 834 - 846
Main Authors:	Greve, Gabriele, Schüler, Julia, Grüning, Björn A, Berberich, Bettina, Stomper, Julia, Zimmer, Dennis, Gutenkunst, Lea, Bönisch, Ulrike, Meier, Ruth, Blagitko-Dorfs, Nadja, Grishina, Olga, Pfeifer, Dietmar, Weichenhan, Dieter, Plass, Christoph, Lübbert, Michael
Format:	Journal Article
Language:	English
Published:	United States 15-02-2021
Subjects:	Animals Azacitidine - pharmacology Decitabine - pharmacology Epigenesis, Genetic Humans Karyotype Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - genetics Mice Monosomy
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Summary:	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 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. .
ISSN:	0008-5472 1538-7445
DOI:	10.1158/0008-5472.CAN-20-1430