Epigenetic agent treatment through reactivation of repressed, haploinsufficient tumour suppressor genes in high-risk AML


Project Summary

Patients with adverse-genetics AML show remarkable responses to DNA-hypomethylating agents such as decitabine (DAC). We hypothesised that haploinsufficiency of tumour suppressor genes in monosomal AML is compounded by epigenetic silencing. We identified several genes, including Endogenous Retrovirus (ERV)3-1, that are preferentially de-repressed by DAC in AML cell lines. We will conduct a systematic analysis of endogenous retroviruses and other transposable elements regulated by DAC in our cell models. We aim to identify predictors of response to this treatment and to unravel non-genetic resistance mechanisms operative in AML blasts.

Selected project-relevant publications

  • Rummelt C., Grishina O., Schmoor C., Crysandt M., Heuser M., Götze K.S., Schlenk R.F., Döhner K., Salih H.R., Heil G., Müller-Tidow C., Brugger W., Kündgen A., De Wit M., Giagounidis A., Scholl S., Neubauer A., Krauter J., Bug G., Al-Ali H.K., Wäsch R., Becker H., May A.M., Duyster J., Hackanson B., Ganser A., Döhner H. and Lübbert M. (2023) Activity of decitabine combined with all-trans retinoic acid in oligoblastic acute myeloid leukemia: results from a randomized 2×2 phase II trial (DECIDER). Haematologica 108, 2244-2248.
  • Greve G., Andrieux G., Schlosser P., Blagitko-Dorfs N., Rehman U.U., Ma T., Pfeifer D., Heil G., Neubauer A., Krauter J., Heuser M., Salih H.R., Döhner K., Döhner H., Hackanson B., Boerries M. and Lübbert M. (2023) In vivo kinetics of early, non-random methylome and transcriptome changes induced by DNA-hypomethylating treatment in primary AML blasts. Leukemia 37, 1018-1027.
  • Blum S., Tsilimidos G., Bresser H. and Lübbert M. (2023) Role of Bcl-2 inhibition in myelodysplastic syndromes. Int J Cancer 152, 1526-1535.
  • Santini V., Lübbert M., Wierzbowska A. and Ossenkoppele G.J. (2022) The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia. Adv Ther 39, 1474-1488.
  • Meier R., Greve G., Zimmer D., Bresser H., Berberich B., Langova R., Stomper J., Rubarth A., Feuerbach L., Lipka D.B., Hey J., Grüning B., Brors B., Duyster J., Plass C., Becker H. and Lübbert M. (2022) The antileukemic activity of decitabine upon PML/RARA-negative AML blasts is supported by all-trans retinoic acid: in vitro and in vivo evidence for cooperation. Blood Cancer J 12, 122.
  • Stomper J., Meier R., Ma T., Pfeifer D., Ihorst G., Blagitko-Dorfs N., Greve G., Zimmer D., Platzbecker U., Hagemeijer A., Schmitt-Gräff A. and Lübbert M. (2021) Integrative study of EZH2 mutational status, copy number, protein expression and H3K27 trimethylation in AML/MDS patients. Clin Epigenetics 13, 77.
  • May A.M., Stomper J., Joeckel T.E., Bronsert P., Wijermans P.W., Werner M. and Lübbert M. (2020) Distinct bone marrow morphologic features discriminate myelodysplastic syndromes patients with and without an early platelet response to decitabine. Br J Haematol 189, e194-e197.
  • Herrlinger E.M., Hau M., Redhaber D.M., Greve G., Willmann D., Steimle S., Müller M., Lübbert M., Miething C.C., Schüle R. and Jung M. (2020) Nitroreductase-Mediated Release of Inhibitors of Lysine-Specific Demethylase 1 (LSD1) from Prodrugs in Transfected Acute Myeloid Leukaemia Cells. Chembiochem 21, 2329-2347.
  • Greve G., Schüler J., Grüning B.A., Berberich B., Stomper J., Zimmer D., Gutenkunst L., Bönisch U., Meier R., Blagitko-Dorfs N., Grishina O., Pfeifer D., Weichenhan D., Plass C. and Lübbert M. (2020) Decitabine induces gene derepression on monosomic chromosomes: in vitro and in vivo effects in adverse-risk cytogenetics AML. Cancer Res, doi 10.1158/0008-5472.can-1120-1430.
  • Becker H., Pfeifer D., Ihorst G., Pantic M., Wehrle J., Rüter B.H., Bullinger L., Hackanson B., Germing U., Kuendgen A., Platzbecker U., Döhner K., Ganser A., Hagemeijer A., Wijermans P.W., Döhner H., Duyster J. and Lübbert M. (2020) Monosomal karyotype and chromosome 17p loss or TP53 mutations in decitabine-treated patients with acute myeloid leukemia. Ann Hematol 99, 1551-1560.
  • Stomper J., Ihorst G., Suciu S., Sander P.N., Becker H., Wijermans P.W., Plass C., Weichenhan D., Bisse E., Claus R. and Lubbert M. (2019) Fetal hemoglobin induction during decitabine treatment of elderly patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: a potential dynamic biomarker of outcome. Haematologica 104, 59-69.
  • Lubbert M., Grishina O., Schmoor C., Schlenk R.F., Jost E., Crysandt M., Heuser M., Thol F., Salih H.R., Schittenhelm M.M., Germing U., Kuendgen A., Gotze K.S., Lindemann H.W., Muller-Tidow C., Heil G., Scholl S., Bug G., Schwaenen C., Giagounidis A., Neubauer A., Krauter J., Brugger W., De Wit M., Wasch R., Becker H., May A.M., Duyster J., Dohner K., Ganser A., Hackanson B. and Dohner H. (2019) Valproate and Retinoic Acid in Combination With Decitabine in Elderly Nonfit Patients With Acute Myeloid Leukemia: Results of a Multicenter, Randomized, 2 x 2, Phase II Trial. J Clin Oncol Jco1901053, doi: 10.1200/JCO.1219.01053.
  • Blagitko-Dorfs N., Schlosser P., Greve G., Pfeifer D., Meier R., Baude A., Brocks D., Plass C. and Lubbert M. (2019) Combination treatment of acute myeloid leukemia cells with DNMT and HDAC inhibitors: predominant synergistic gene downregulation associated with gene body demethylation. Leukemia 33, 945-956.
  • Becker H., Greve G., Kataoka K., Mallm J.P., Duque-Afonso J., Ma T., Niemoller C., Pantic M., Duyster J., Cleary M.L., Schuler J., Rippe K., Ogawa S. and Lubbert M. (2019) Identification of enhancer of mRNA decapping 4 as a novel fusion partner of MLL in acute myeloid leukemia. Blood Adv 3, 761-765.
  • Flotho C., Sommer S. and Lubbert M. (2018) DNA-hypomethylating agents as epigenetic therapy before and after allogeneic hematopoietic stem cell transplantation in myelodysplastic syndromes and juvenile myelomonocytic leukemia. Semin Cancer Biol 51, 68-79.
  • Blum S., Greve G. and Lubbert M. (2017) Innovative strategies for adverse karyotype acute myeloid leukemia. Curr Opin Hematol 24, 89-98.
  • Schiffmann I., Greve G., Jung M. and Lubbert M. (2016) Epigenetic therapy approaches in non-small cell lung cancer: Update and perspectives. Epigenetics 11, 858-870.
  • Morera L., Lubbert M. and Jung M. (2016) Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy. Clin Epigenetics 8, 57.
  • Lubbert M., Suciu S., Hagemeijer A., Ruter B., Platzbecker U., Giagounidis A., Selleslag D., Labar B., Germing U., Salih H.R., Muus P., Pfluger K.H., Schaefer H.E., Bogatyreva L., Aul C., De Witte T., Ganser A., Becker H., Huls G., Van Der Helm L., Vellenga E., Baron F., Marie J.P. and Wijermans P.W. (2016) Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group. Ann Hematol 95, 191-199.
  • Lubbert M. and Kuendgen A. (2015) Combining DNA methyltransferase and histone deacetylase inhibition to treat acute myeloid leukemia/myelodysplastic syndrome: achievements and challenges. Cancer 121, 498-501.
  • Greve G., Schiffmann I., Pfeifer D., Pantic M., Schuler J. and Lubbert M. (2015) The pan-HDAC inhibitor panobinostat acts as a sensitizer for erlotinib activity in EGFR-mutated and -wildtype non-small cell lung cancer cells. BMC Cancer 15, 947.
  • Greve G., Schiffmann I. and Lubbert M. (2015) Epigenetic priming of non-small cell lung cancer cell lines to the antiproliferative and differentiating effects of all-trans retinoic acid. J Cancer Res Clin Oncol 141, 2171-2180.
  • Meidhof S., Brabletz S., Lehmann W., Preca B.T., Mock K., Ruh M., Schuler J., Berthold M., Weber A., Burk U., Lubbert M., Puhr M., Culig Z., Wellner U., Keck T., Bronsert P., Kusters S., Hopt U.T., Stemmler M.P. and Brabletz T. (2015) ZEB1-associated drug resistance in cancer cells is reversed by the class I HDAC inhibitor mocetinostat. EMBO Mol Med 7, 831-847.
  • Navada S.C., Steinmann J., Lubbert M. and Silverman L.R. (2014) Clinical development of demethylating agents in hematology. J Clin Invest 124, 40-46.