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Imprint of 5-azacytidine on the natural killer cell repertoire during systemic treatment for high-risk myelodysplastic syndrome.

ABSTRACT: 5-azacytidine (5-aza) is a hypomethylating agent approved for the treatment of high-risk myelodysplastic syndrome (MDS). It is assumed to act by demethylating tumor suppressor genes and via direct cytotoxic effects on malignant cells. In vitro treatment with hypomethylating agents has profound effects on the expression of killer-cell immunoglobulin-like (KIR) receptors on natural killer (NK) cells, as these receptors are epigenetically regulated via methylation of the promoters. Here we investigated the influence of 5-aza on the NK-cell repertoire during cytokine-induced proliferation in vitro and homeostatic proliferation in vivo in patients with high-risk MDS. In vitro treatment of NK cells from both healthy donors and MDS patients with low doses of 5-aza led to a significant increase in expression of multiple KIRs, but only in cells that had undergone several rounds of cell division. Proliferating 5-aza exposed NK cells exhibited increased IFN-? production and degranulation towards tumor target cells. MDS patients had lower proportions of educated KIR-expressing NK cells than healthy controls but after systemic treatment with 5-aza, an increased proportion of Ki-67+ NK cells expressed multiple KIRs suggesting uptake of 5-aza in cycling cells in vivo. Hence, these results suggest that systemic treatment with 5-aza may shape the NK cell repertoire, in particular during homeostatic proliferation, thereby boosting NK cell-mediated recognition of malignant cells.

SUBMITTER: Sohlberg E

PROVIDER: S-EPMC4741444 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Imprint of 5-azacytidine on the natural killer cell repertoire during systemic treatment for high-risk myelodysplastic syndrome.

Sohlberg Ebba E Pfefferle Aline A Andersson Sandra S Baumann Bettina C BC Hellström-Lindberg Eva E Malmberg Karl-Johan KJ

Oncotarget 20151001 33

5-azacytidine (5-aza) is a hypomethylating agent approved for the treatment of high-risk myelodysplastic syndrome (MDS). It is assumed to act by demethylating tumor suppressor genes and via direct cytotoxic effects on malignant cells. In vitro treatment with hypomethylating agents has profound effects on the expression of killer-cell immunoglobulin-like (KIR) receptors on natural killer (NK) cells, as these receptors are epigenetically regulated via methylation of the promoters. Here we investig ...[more]

PMID: 26497557

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Project description:Therapy and outcome for elderly acute myeloid leukemia (AML) patients has not improved for many years. Similarly, there remains a clinical need to improve response rates in advanced myelodysplastic syndrome (MDS) patients treated with hypomethylating agents, and few combination regimens have shown clinical benefit. We conducted a 5-azacytidine (5-Aza) RNA-interference (RNAi) sensitizer screen to identify gene targets within the commonly deleted regions (CDRs) of chromosomes 5 and 7, whose silencing enhances the activity of 5-Aza.An RNAi silencing screen of 270 genes from the CDRs of chromosomes 5 and 7 was performed in combination with 5-Aza treatment in four AML cell lines (TF-1, THP-1, MDS-L, and HEL). Several genes within the hedgehog pathway (HhP), specifically SHH, SMO, and GLI3, were identified as 5-Aza sensitizing hits. The smoothened (SMO) inhibitors LDE225 (erismodegib) and GDC0449 (vismodegib) showed moderate single-agent activity in AML cell lines. Further studies with erismodegib in combination with 5-Aza demonstrated synergistic activity with combination index (CI) values of 0.48 to 0.71 in seven AML lines. Clonogenic growth of primary patient samples was inhibited to a greater extent in the combination than with single-agent erismodegib or 5-Aza in 55 % (6 of 11) primary patient samples examined. There was no association of the 5-Aza/erismodegib sensitization potential to clinical-cytogenetic features or common myeloid mutations. Activation of the HhP, as determined by greater expression of HhP-related genes, showed less responsiveness to single-agent SMO inhibition, while synergy between both agents was similar regardless of HhP gene expression. In vitro experiments suggested that concurrent dosing showed stronger synergy than sequential dosing.Inhibition of the HhP with SMO inhibitors in combination with the hypomethylating agent 5-Aza demonstrates synergy in vitro and inhibits long-term repopulation capacity ex vivo in AML and MDS. A clinical trial combining 5-Aza with LDE225 (erismodegib) in MDS and AML is ongoing based on these results as well as additional publications suggesting a role for HhP signaling in myeloid disease.

Dataset Information

Imprint of 5-azacytidine on the natural killer cell repertoire during systemic treatment for high-risk myelodysplastic syndrome.

Publications

Imprint of 5-azacytidine on the natural killer cell repertoire during systemic treatment for high-risk myelodysplastic syndrome.

Similar Datasets

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