Professor Christian Flotho
T: (00) 49 (0)761 270 46 280
F: (00) 49 (0)761 270 46 282
Medical Center – University of Freiburg
Center for Pediatrics
Department of Pediatric Hematology and Oncology
Juvenile myelomonocytic leukemia (JMML) is a malignant myeloproliferative disorder of early childhood. The central aim of our research is the elucidation of the early epigenetic dynamics in JMML through integrated global and focal DNA methylation profiling, transcriptome analysis and mass spectrometric proteomics, both in patient-derived xenograft models and in primary clinical material.
- Dr. rer. nat. Lorena Gallego-Villar (Postdoc)
- Dr. rer. nat. Zoé Wehbe (Postdoc)
- Dr. rer. nat. Foued Ghanjati (Postdoc)
- Alisa Volz (technician)
- Rieke Schröder (MD student)
JMML is an aggressive mixed myeloproliferative/myelodysplastic neoplasm that occurs mainly in young children. Although allogeneic hematopoietic stem cell transplantation (HSCT) is still the mainstay of successful therapy, it is associated with considerable toxicity and a high risk of failure. Accordingly, we aim to understand the mechanisms regulating treatment resistance and relapse of the disease.
Our previous studies have confirmed the involvement of epigenetic mechanisms in the etiopathogenesis of JMML. The most common epigenetic alteration involves cytosine hypermethylation at 5‘ genetic regions, already considered a hallmark of high-risk JMML. Therefore, the characterization of disordered global and focal DNA methylation and its consequences will contribute to better diagnosis and management of JMML.
Specifically, we use our established xenograft model to functionally analyse the clonal epigenetic architecture and intra-patient diversity in JMML patients, along with its changes before and after treatment with DNA methyltransferase inhibitors such as azacitidine. Furthermore, we aim to integrate genome-wide DNA methylation profiles and alterations in the transcriptome and proteome. The efficacy of azacitidine for treatment of JMML was demonstrated and confirmed in a multicenter, international, phase 2 clinical trial (AZA-JMML 001, registered as a Pediatric Investigation Plan with the European Medicines Agency), for which our institution provided central medical coordination, reference diagnostics, and pharmacodynamic studies. In an ancillary study to this trial, we focus on understanding the early cellular effects of DNA hypomethylation in JMML by integrated DNA methylation profiling, transcriptome analysis, and mass-spectrometry proteomics.
SELECTED RECENT PUBLICATIONS
- Niemeyer C.M. and Flotho C. (2019) Juvenile myelomonocytic leukemia: who’s the driver at the wheel? Blood 133, 1060-1070. DOI: 10.1182/blood-2018-11-844688
- 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. DOI: 10.1038/s41375-018-0343-2
- 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. DOI: 10.1016/j.semcancer.2017.10.011
- 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. (*jointly supervised this work). DOI: 10.1038/s41467-017-02177-w
- 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. (*contributed equally to this work). DOI: 10.3324/haematol.2015.138545
- 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. DOI: 10.1182/blood-2015-01-619734
COLLABORATIONS, CO-OPERATIONS AND NETWORKS
- DFG Collaborative Research Center 992 “Medical Epigenetics”
- BMBF consortium „MyPred“ (Information in German)