EPIdiagnosis and EPItherapy of juvenile myelomonocytic leukemia

EPIdiagnosis and EPItherapy of juvenile myelomonocytic leukemia2024-01-26T09:55:52+01:00

Professor Christian Flotho

E: christian.flotho@uniklinik-freiburg.de
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
Mathildenstraße 1
79106 Freiburg

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. Zoé Wehbe (Postdoc)
  • Dr. rer. nat. Foued Ghanjati (Postdoc)
  • Dr. rer. nat. Khaled Alatibi (Postdoc)
  • Melanie Guimaraes Moreira (Technician)
  • Marlou Schoof (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. The efficacy of the DNA methyltransferase inhibitor 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; EudraCT 2014‐002388‐13 and NCT 02447666), 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 integrating DNA methylation profiling, transcriptome analysis, and mass-spectrometry proteomics. We anticipate that the characterization of disordered global and focal DNA methylation and its consequences will contribute to better diagnosis and management of JMML.

The nature of JMML-initiating cells, the cellular hierarchy, and the clonal architecture of the malignant cells remain poorly characterized. Our current work addresses the role of intratumoral clonal diversity in disease progression and treatment resistance in JMML. We hypothesize that the early presence of cell subpopulations that give rise to therapy-resistant cell clones is a key factor determining the risk of progression or relapse and hence the ultimate outcome. While previous characterization of the genetic landscape in JMML was based on bulk leukemic cell samples, we now create genetic maps at the single-cell level in samples from a well-documented patient cohort and associate these with hematologic and clinical information.

To expand the possibilities of modeling the disease for translational research, we reprogram induced pluripotent stem cells (IPSCs) from JMML bone marrow cells of various genotypes and epigenotypes and redifferentiate these cells into hematopoietic lineages. This will allow using the lines for preclinical testing of novel therapeutic principles, for example substances targeting the leukemic cell metabolism at the level of oxidative phosphorylation.




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