Juvenile myelomonocytic leukemia (JMML) is a rare blood cancer of early childhood. Previous research activities have shown that JMML patients can be divided into three groups based on certain genetic markers, DNA methylation. Depending on the subgroup, statements can be made about the course of the disease.
Scientists of the German Cancer Research Center (DKFZ), the National Center for Tumor Diseases (NCT) Heidelberg and the Medical Center University of Freiburg, together with international colleagues, have now defined a globally valid uniform methodology for the use of methylation status as a biomarker in JMML based on a database of 255 patients. The classification method is designed to be used in everyday clinical practice. One of the aims of the researchers is to identify high-risk patients more quickly in order to give them access to innovative treatments in clinical studies.The National Center for Tumor Diseases (NCT) Heidelberg is a joint institution of the German Cancer Research Center (DKFZ), Heidelberg University Hospital (UKHD) and German Cancer Aid (DKH).Juvenile myelomonocytic leukemia (JMML) mainly affects children, usually before the end of the second year of life. So far, blood stem cell transplantation is the only form of treatment. If this therapy is not successful, the disease is often fatal.Researchers have found out that the development of cancer is not only a purely genetic process. Markers on the genetic material can also promote the uncontrolled growth of cells. Scientists have therefore also examined the genetic material of JMML cells for the occurrence of certain chemical genetic markers, DNA methylation. These so-called epigenetic changes control the activity of individual genes. "Depending on how strongly the DNA is methylated, JMML patients can be divided into three groups: Patients in whom the genetic material of the tumor cells is strongly methylated usually show characteristics that are associated with an increased risk of relapse after stem cell transplantation. In another group of patients whose tumor genome is only weakly methylated, the disease usually progresses milder. A third group has a medium level of DNA methylation," reports Daniel Lipka, head of the Section Translational Cancer Epigenomics in the Department of Translational Medical Oncology at DKFZ and the NCT Heidelberg. The analysis of DNA methylation status is therefore now also used as a biomarker to better assess the course of disease in JMML patients.In the present study, international scientists and physicians have defined a standardized methodology for subgrouping JMML based on the DNA methylation pattern. For this purpose, the genetic analyses of 255 patients were evaluated and clinically and biologically characterized. "Our analysis was able to detect the methylation pattern as the only significant factor that can predict overall survival in this particular disease," reports Maximilian Schönung, first author of the publication and scientist in the Section Translational Cancer Epigenomics of the Department of Translational Medical Oncology at DKFZ and at the NCT Heidelberg. The researchers tested the method in an independent patient group and also investigated whether the analyses produce reliable results at different locations and with different technical conditions. The results of the group classification were in 98 percent agreement and thus proved the high reliability of the classification method. "Thanks to the international standard procedure, JMML patients can now be more reliably assigned to the three subgroups. In particular, high-risk patients for whom an allogeneic blood stem cell transplantation is not curative can now be identified more quickly," says Christian Flotho, scientist in the German Consortium for Translational Cancer Research (DKTK) at the University of Freiburg Medical Center. "For this challenging group of patients, we are working together with the European study group EWOG-MDS to develop clinical studies that will open up access to innovative treatment options," adds Lipka.
M. Schönung, J. Meyer, P. Nöllke, A. Olshen, M. Hartmann, N. Murakami, M. Wakamatsu, Y. Okuno, C. Plass, M. Loh, C. M. Niemeyer, H. Muramatsu, C. Flotho, E. Stieglitz, D. B. Lipka: International consensus definition of DNA methylation subgroups in juvenile myelomonocytic leukemia. CCR, DOI: 10.1158/1078-0432.CCR-20-3184