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Researchers at the National Center for Tumor Diseases (NCT) Heidelberg and the German Cancer Research Center (DKFZ) have gained new insights into how a certain type of early childhood leukemia develops: Leukemia cells can reactivate certain programs from fetal development, especially in aggressive forms of the disease. The findings open up new avenues for diagnosis and therapy.

The National Center for Tumor Diseases (NCT) Heidelberg is a joint institution of the German Cancer Research Center (DKFZ), Heidelberg University Hospital (UKHD), Heidelberg University Medical Faculty, and Heidelberg Thorax Clinic.

Until now, it was assumed that fetal, i.e., prenatal genetic changes in childhood tumors block the maturation of stem cells, thereby permanently preserving fetal developmental programs. This model was intended to explain why these tumors exhibit molecular patterns that typically occur before birth but no longer in childhood.

Contrary to this well-known model, researchers at the NCT Heidelberg and the DKFZ found a surprising interaction between two processes in juvenile myelomonocytic leukemia (JMML), a rare early childhood leukemia with sometimes highly aggressive courses: On the one hand, epigenetic patterns in leukemia stem cells continued to show age-appropriate maturation. On the other hand, stem cell programs at different stages of development were active in parallel in the same cells, indicating their disease-related reactivation. The researchers found a strong reactivation of fetal stem cell programs, particularly in aggressive forms of JMML.

The simultaneous activity of different developmental programs in this type of leukemia is an expression of exceptionally strong molecular plasticity. The phenomenon of molecular plasticity is associated with many adult cancers that are particularly aggressive, but this form has not previously been known in childhood cancers.

The study thus significantly expands the existing model. First author Mark Hartmann, Section Translational Cancer Epigenomics in the Department of Translational Medical Oncology at the DKFZ and NCT Heidelberg, explains: “Early childhood leukemias do not always show a maturation block in the prenatal state; rather, fetal programs in leukemia stem cells can also arise through later reactivation after birth.” Further studies are needed to investigate whether this principle also applies to other types of childhood cancer.

Among the reactivated programs, the cell surface molecule CD52 was particularly noteworthy: In JMML, it is found to a particularly high degree on leukemia stem cells in high-risk patients and offers a promising therapeutic target, as it is not found on healthy blood stem cells. Maximilian Schönung, Section Translational Cancer Epigenomics in the Department of Translational Medical Oncology at the DKFZ and NCT Heidelberg, also first author of the study, says: “In mice, we were able to significantly slow down the progression of the disease with an antibody directed against CD52 and even completely eliminate the leukemia stem cells.”

The study highlights the importance of understanding the different developmental programs of normal blood stem cells. This is the only way to accurately identify pathological changes in early childhood leukemia. Daniel Lipka, head of the Translational Cancer Epigenomics Section in the Department of Translational Medical Oncology at the DKFZ and NCT Heidelberg, is the senior author of the publication. He says: “Our results show that aggressive childhood leukemias are not necessarily based on a maturation block in blood stem cells in the womb. Rather, cancer-promoting mutations can alter the molecular identity of already mature blood stem cells to such an extent that they revert to a fetal state – this knowledge opens up new therapeutic options for us.”

Publication: 
Mark Hartmann, Maximilian Schönung, Jovana Rajak, Valentin Maurer, Ling Hai, Katharina Bauer, Mariam Hakobyan, Sina Stäble, Jen Langstein, Laura Jardine, Roland Roelz, Sheila Bohler, Eleonora Khabirova, Abdul-Habib Maag, Dominik Vonficht, Dirk Lebrecht, Kathrin M. Bernt, Kai Tan, Changya Chen, Fatemeh Alikarami, Julia Meyer, Jun Wang, Tobias Boch, Viktoria Flore, Pavlo Lutsik, Michael D. Milsom, Simon Raffel, Christian Buske, Simon Haas, Muzlifah Haniffa, Jan-Philipp Mallm, Sam Behjati, Marc-Jan Bonder, Stefan Fröhling, Elliot Stieglitz, Charlotte M. Niemeyer, Joschka Hey, Christian Flotho, Christoph Plass, Miriam Erlacher, Matthias Schlesner, Daniel B. Lipka: Molecular Plasticity Results in Oncofetal Reprogramming and Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia. Blood Cancer Discovery; doi.org/10.1158/2643-3230.BCD-25-0246

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https://www.nct-heidelberg.de/fileadmin/media/nct-heidelberg/news/pressemitteilungen/Presseinfo_UMAP_JMML.jpg

Image description:
The UMAP (Uniform Manifold Approximation and Projection) maps complex single-cell transcriptome data in two dimensions so that similar hematopoietic cells are close to each other. Each point represents a cell, and the color indicates its cell type or cell state as determined by gene activity.

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Press contact:
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National Center for Tumor Diseases (NCT) Heidelberg
Communications and Events
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69120 Heidelberg, Germany
Tel.: +49 6221 56-311272
Email: martin.staiger(at)nct-heidelberg.de
www.nct-heidelberg.de

The National Center for Tumor Diseases (NCT) Heidelberg

The National Center for Tumor Diseases (NCT) Heidelberg is a joint institution of the German Cancer Research Center (DKFZ), the University Hospital Heidelberg (UKHD), the Heidelberg Medical Faculty of the Heidelberg University and the Thoraxklinik Heidelberg. The aim of the NCT Heidelberg is to transfer promising approaches from cancer research into clinical practice as quickly as possible, and thus to benefit patients. This applies to both diagnosis and treatment, in aftercare or prevention. Participation in clinical studies opens up access to innovative therapies. The NCT Heidelberg is thus a leader in transferring new research results from the laboratory to the clinic The NCT Heidelberg, founded in 2004, is part of the NCT with further locations in Berlin, Dresden, SouthWest (Tübingen-Stuttgart/Ulm), WERA (Würzburg, Erlangen, Regensburg, Augsburg) and West (Essen/Cologne).
 

German Cancer Research Center (DKFZ)

With more than 3,000 employees, the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) is Germany’s largest biomedical research institute. DKFZ scientists identify cancer risk factors, investigate how cancer progresses and develop new cancer prevention strategies. They are also developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to questions relating to cancer.

To transfer promising approaches from cancer research to the clinic and thus improve the prognosis of cancer patients, the DKFZ cooperates with excellent research institutions and university hospitals throughout Germany:

• National Center for Tumor Diseases (NCT, 6 sites)  
• German Cancer Consortium (DKTK, 8 sites)
• Hopp Children's Cancer Center (KiTZ) Heidelberg
• Helmholtz Institute for Translational Oncology (HI-TRON Mainz) - A Helmholtz Institute of the DKFZ
• DKFZ-Hector Cancer Institute at the University Medical Center Mannheim
• National Cancer Prevention Center (jointly with German Cancer Aid) 

The DKFZ is 90 percent financed by the Federal Ministry of Research, Technology and Space and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.

Heidelberg University Hospital and Faculty of Medicine: Internationally Renowned Patient Care, Research and Teaching

Heidelberg University Hospital (Universitätsklinikum Heidelberg, UKHD) is one of the largest and most prestigious medical centers in Germany. The Medical Faculty of Heidelberg University (Medizinische Fakultät Heidelberg, MFHD) belongs to the internationally renowned biomedical research institutions in Europe. Both institutions have the common goal of developing new therapies and implementing them rapidly for patients. Heidelberg University Hospital and the Medical Faculty of Heidelberg University employs around 14.500 employees and is committed to providing trainings and qualifications. Every year, around 86,000 patients and more than 1.100.000 outpatient cases are treated in more than 50 clinical departments with almost 2.500 beds.

Together with the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and the German Cancer Aid, the UKHD established the first National Center for Tumor Diseases (NCT) in Heidelberg. The goal is to provide care at the highest level as an oncology center of excellence and to rapidly transfer promising approaches from cancer research to the hospital. In addition, the UKHD operates in partnership with the DKFZ and the University of Heidelberg the Hopp Children’s Cancer center Heidelberg (KiTZ), a unique and nationally known therapy and research center for oncological and hematological diseases in children and adolescents.

The Heidelberg Curriculum Medicinale (HeiCuMed) is one of the top medical training programs in Germany. Currently, there are about 4.000 future physicians studying in Heidelberg.