Johannes Lorenz Berg1, Bianca Perfler1, Stefan Hatzl1, Marie-Christina Mayer1, Sonja Wurm1, Barbara Uhl1, Andreas Reinisch1, Ingeborg Klymiuk2, Sascha Tierling3, Gudrun Pregartner4, Gerhard Bachmaier4, Andrea Berghold4, Klaus Geissler5,6, Martin Pichler7,8, Gerald Hoefler9, Herbert Strobl10, Albert Wölfler1, Heinz Sill1, Armin Zebisch11,12. 1. Division of Hematology, Medical University of Graz, Auenbruggerplatz 38, 8036, Graz, Austria. 2. Core Facility Molecular Biology, Medical University of Graz, Graz, Austria. 3. Department of Genetics, University of Saarland, Saarbrücken, Germany. 4. Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria. 5. 5th Medical Department with Hematology, Oncology and Palliative Medicine, Hospital Hietzing, Vienna, Austria. 6. Sigmund Freud University, Vienna, Austria. 7. Division of Oncology, Medical University of Graz, Graz, Austria. 8. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Centre, Houston, TX, USA. 9. Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria. 10. Otto Loewi Research Centre, Immunology and Pathophysiology, Medical University of Graz, Graz, Austria. 11. Division of Hematology, Medical University of Graz, Auenbruggerplatz 38, 8036, Graz, Austria. armin.zebisch@medunigraz.at. 12. Otto-Loewi Research Centre for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010, Graz, Austria. armin.zebisch@medunigraz.at.
Abstract
BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: Taken together, we report decreased expression of miR-125a in CMML and delineate its relevance as mediator of HMA efficacy within this neoplasia.
BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: Taken together, we report decreased expression of miR-125a in CMML and delineate its relevance as mediator of HMA efficacy within this neoplasia.
Authors: A Zebisch; A Wölfler; I Fried; O Wolf; K Lind; C Bodner; M Haller; A Drasche; D Pirkebner; D Matallanas; O Rath; K Blyth; R Delwel; E Taskesen; F Quehenberger; W Kolch; J Troppmair; H Sill Journal: Leukemia Date: 2012-03-05 Impact factor: 11.528
Authors: N Tatsumi; N Hojo; O Yamada; M Ogawa; Y Katsura; S Kawata; E Morii; H Sakamoto; R Inaba; A Tsuda; I Fukuda; N Moriguchi; H Hasuwa; M Okabe; F Fujiki; S Nishida; H Nakajima; A Tsuboi; Y Oka; N Hosen; H Sugiyama; Y Oji Journal: Oncogene Date: 2015-05-11 Impact factor: 9.867
Authors: C Flotho; R Claus; C Batz; M Schneider; I Sandrock; S Ihde; C Plass; C M Niemeyer; M Lübbert Journal: Leukemia Date: 2009-02-05 Impact factor: 11.528
Authors: Zhi Hong Fang; Si Li Wang; Jin Tao Zhao; Zhi Juan Lin; Lin Yan Chen; Rui Su; Si Ting Xie; Bing Z Carter; Bing Xu Journal: Cell Death Dis Date: 2016-09-22 Impact factor: 8.469
Authors: Raphael Itzykson; Pierre Fenaux; David Bowen; Nicholas C P Cross; Jorge Cortes; Theo De Witte; Ulrich Germing; Francesco Onida; Eric Padron; Uwe Platzbecker; Valeria Santini; Guillermo F Sanz; Eric Solary; Arjan Van de Loosdrecht; Luca Malcovati Journal: Hemasphere Date: 2018-11-29
Authors: Katharina T Prochazka; Gudrun Pregartner; Frank G Rücker; Ellen Heitzer; Gabriel Pabst; Albert Wölfler; Armin Zebisch; Andrea Berghold; Konstanze Döhner; Heinz Sill Journal: Haematologica Date: 2018-10-11 Impact factor: 9.941
Authors: Javier C Angulo; Claudia Manini; Jose I López; Angel Pueyo; Begoña Colás; Santiago Ropero Journal: Cancers (Basel) Date: 2021-04-25 Impact factor: 6.639
Authors: Mohammad Taheri; Dominik A Barth; Julia Kargl; Omidvar Rezaei; Soudeh Ghafouri-Fard; Martin Pichler Journal: Front Immunol Date: 2021-11-04 Impact factor: 7.561