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Berg, JL; Perfler, B; Hatzl, S; Mayer, MC; Wurm, S; Uhl, B; Reinisch, A; Klymiuk, I; Tierling, S; Pregartner, G; Bachmaier, G; Berghold, A; Geissler, K; Pichler, M; Hoefler, G; Strobl, H; Wölfler, A; Sill, H; Zebisch, A.
Micro-RNA-125a mediates the effects of hypomethylating agents in chronic myelomonocytic leukemia.
Clin Epigenetics. 2021; 13(1): 1-1. Doi: 10.1186/s13148-020-00979-2 [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz
Zebisch Armin
Co-Autor*innen der Med Uni Graz
Bachmaier Gerhard
Berg Johannes Lorenz
Berghold Andrea
Hatzl Stefan
Höfler Gerald
Klymiuk Ingeborg
Mayer Marie-Christina
Perfler Bianca
Pichler Martin
Pregartner Gudrun
Reinisch Andreas
Sill Heinz
Strobl Herbert
Uhl Barbara
Wölfler Albert
Wurm Sonja

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Chronic myelomonocytic leukemia (CMML) is an aggressive hematopoietic malignancy that arises from hematopoietic stem and progenitor cells (HSPCs). Patients with CMML are frequently treated with epigenetic therapeutic approaches, in particular the hypomethylating agents (HMAs), azacitidine (Aza) and decitabine (Dec). Although HMAs are believed to mediate their efficacy via re-expression of hypermethylated tumor suppressors, knowledge about relevant HMA targets is scarce. As silencing of tumor-suppressive micro-RNAs (miRs) by promoter hypermethylation is a crucial step in malignant transformation, we asked for a role of miRs in HMA efficacy in CMML. Initially, we performed genome-wide miR-expression profiling in a KrasG12D-induced CMML mouse model. Selected candidates with prominently decreased expression were validated by qPCR in CMML mice and human CMML patients. These experiments revealed the consistent decrease in miR-125a, a miR with previously described tumor-suppressive function in myeloid neoplasias. Furthermore, we show that miR-125a downregulation is caused by hypermethylation of its upstream region and can be reversed by HMA treatment. By employing both lentiviral and CRISPR/Cas9-based miR-125a modification, we demonstrate that HMA-induced miR-125a upregulation indeed contributes to mediating the anti-leukemic effects of these drugs. These data were validated in a clinical context, as miR-125a expression increased after HMA treatment in CMML patients, a phenomenon that was particularly pronounced in cases showing clinical response to these drugs. Taken together, we report decreased expression of miR-125a in CMML and delineate its relevance as mediator of HMA efficacy within this neoplasia.

Find related publications in this database (Keywords)
Chronic myelomonocytic leukemia
Hypomethylating agent
Tumor suppressor
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