Targeting disease-causing cells by DNA hypomethylation in juvenile myelomonocytic leukaemia

Project Summary

Juvenile myelomonocytic leukaemia (JMML) is a myeloproliferative disorder of early childhood and it is standard practice to prepare every patient for a haematopoietic stem cell transplant (HSCT) as the only curative therapy. However, the risk of relapse is high. We will characterise the early cellular effects of DNA hypomethylation in JMML leukaemia-initiating cells (LICs) by integrated DNA methylation profiling in our xenograft model, and will validate their clinical significance in primary patient material. Our ultimate goal is to identify mechanisms that help to overcome resistance of JMML LICs to azacitidine and HSCT.

Selected project-relevant publications

• Vinci L., Flotho C., Noellke P., Lebrecht D., Masetti R., De Haas V., De Moerloose B., Dworzak M., Hasle H., Güngör T., Starý J., Turkiewicz D., Ussowicz M., De Heredia C.D., Buechner J., Jahnukainen K., Kallay K., Bodova I., Smith O.P., Zecca M., Bresters D., Lang P., Masmas T.N., Meisel R., Pichler H., Erlacher M., Göhring G., Locatelli F., Strahm B., Niemeyer C.M. and Yoshimi A. (2023) Second allogeneic stem cell transplantation can rescue a significant proportion of patients with JMML relapsing after first allograft. Bone Marrow Transplant 58, 607-609.
• Schröder R., Illert A.L., Erbes T., Flotho C., Lübbert M. and Duque-Afonso J. (2022) The epigenetics of breast cancer – Opportunities for diagnostics, risk stratification and therapy. Epigenetics 17, 612-624.
• Wehbe Z., Ghanjati F. and Flotho C. (2021) Induced Pluripotent Stem Cells to Model Juvenile Myelomonocytic Leukemia: New Perspectives for Preclinical Research. Cells 10, doi 10.3390/cells10092335.
• Niemeyer C.M., Flotho C., Lipka D.B., Starý J., Rössig C., Baruchel A., Klingebiel T., Micalizzi C., Michel G., Nysom K., Rives S., Schmugge Liner M., Zecca M., Schönung M., Baumann I., Nöllke P., Benettaib B., Biserna N., Poon J., Simcock M., Patturajan M., Menezes D., Gaudy A., Van Den Heuvel-Eibrink M.M. and Locatelli F. (2021) Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial. Blood Adv 5, 2901-2908.
• Mayerhofer C., Niemeyer C.M. and Flotho C. (2021) Current Treatment of Juvenile Myelomonocytic Leukemia. J Clin Med 10, doi 10.3390/jcm10143084.
• Hofmans M., Lammens T., Depreter B., Wu Y., Erlacher M., Caye A., Cavé H., Flotho C., De Haas V., Niemeyer C.M., Stary J., Van Nieuwerburgh F., Deforce D., Van Loocke W., Van Vlierberghe P., Philippé J. and De Moerloose B. (2021) Long non-coding RNAs as novel therapeutic targets in juvenile myelomonocytic leukemia. Sci Rep 11, 2801.
• Schönung M., Meyer J., Nöllke P., Olshen A.B., Hartmann M., Murakami N., Wakamatsu M., Okuno Y., Plass C., Loh M.L., Niemeyer C.M., Muramatsu H., Flotho C., Stieglitz E. and Lipka D.B. (2020) International consensus definition of DNA methylation subgroups in juvenile myelomonocytic leukemia. Clin Cancer Res, doi: 10.1158/1078-0432.ccr-1120-3184.
• Niemeyer C.M. and Flotho C. (2019) Juvenile myelomonocytic leukemia: who’s the driver at the wheel? Blood 133, 1060-1070.
• Krombholz C.F., Gallego-Villar L., Sahoo S.S., Panda P.K., Wlodarski M.W., Aumann K., Hartmann M., Lipka D.B., Daskalakis M., Plass C., Niemeyer C.M., Erlacher M. and Flotho C. (2019) Azacitidine is effective for targeting leukemia-initiating cells in juvenile myelomonocytic leukemia. Leukemia 33, 1805-1810.
• Flotho C. (2019) Gene mutations do not operate in a vacuum: the increasing importance of epigenetics in juvenile myelomonocytic leukemia. Epigenetics 14, 236-244.
• 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.
• Lipka D.B., Witte T., Toth R., Yang J., Wiesenfarth M., Nollke P., Fischer A., Brocks D., Gu Z., Park J., Strahm B., Wlodarski M., Yoshimi A., Claus R., Lubbert M., Busch H., Boerries M., Hartmann M., Schonung M., Kilik U., Langstein J., Wierzbinska J.A., Pabst C., Garg S., Catala A., De Moerloose B., Dworzak M., Hasle H., Locatelli F., Masetti R., Schmugge M., Smith O., Stary J., Ussowicz M., Van Den Heuvel-Eibrink M.M., Assenov Y., Schlesner M., Niemeyer C., Flotho C. and Plass C. (2017) RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia. Nat Commun 8, 2126.
• Fluhr S., Krombholz C.F., Meier A., Epting T., Mucke O., Plass C., Niemeyer C.M. and Flotho C. (2017) Epigenetic dysregulation of the erythropoietic transcription factor KLF1 and the beta-like globin locus in juvenile myelomonocytic leukemia. Epigenetics 12, 715-723.
• Wilhelm T., Lipka D.B., Witte T., Wierzbinska J.A., Fluhr S., Helf M., Mucke O., Claus R., Konermann C., Nollke P., Niemeyer C.M., Flotho C. and Plass C. (2016) Epigenetic silencing of AKAP12 in juvenile myelomonocytic leukemia. Epigenetics 11, 110-119.
• Krombholz C.F., Aumann K., Kollek M., Bertele D., Fluhr S., Kunze M., Niemeyer C.M., Flotho C. and Erlacher M. (2016) Long-term serial xenotransplantation of juvenile myelomonocytic leukemia recapitulates human disease in Rag2-/-gammac-/- mice. Haematologica 101, 597-606.
• Fluhr S., Boerries M., Busch H., Symeonidi A., Witte T., Lipka D.B., Mucke O., Nollke P., Krombholz C.F., Niemeyer C.M., Plass C. and Flotho C. (2016) CREBBP is a target of epigenetic, but not genetic, modification in juvenile myelomonocytic leukemia. Clin Epigenetics 8, 50.
• Cseh A.M., Niemeyer C.M., Yoshimi A., Catala A., Fruhwald M.C., Hasle H., Van Den Heuvel-Eibrink M.M., Lauten M., De Moerloose B., Smith O.P., Bernig T., Gruhn B., Kulozik A.E., Metzler M., Olcay L., Suttorp M., Furlan I., Strahm B. and Flotho C. (2016) Therapy with low-dose azacitidine for MDS in children and young adults: a retrospective analysis of the EWOG-MDS study group. Br J Haematol 172, 930-936.
• Cseh A., Niemeyer C.M., Yoshimi A., Dworzak M., Hasle H., Van Den Heuvel-Eibrink M.M., Locatelli F., Masetti R., Schmugge M., Gross-Wieltsch U., Candas A., Kulozik A.E., Olcay L., Suttorp M., Furlan I., Strahm B. and Flotho C. (2015) Bridging to transplant with azacitidine in juvenile myelomonocytic leukemia: a retrospective analysis of the EWOG-MDS study group. Blood 125, 2311-2313.