The FLT3 receptor regulates cell growth, while activating gene mutations promote the uncontrolled proliferation of white blood cells. These findings were reported in the specialist journal Blood by a group of scientists from the Helmholtz Zentrum München and the Hospital of the Ludwig Maximilians University (LMU) in Munich as part of a clinical research collaboration with the German Cancer Consortium (DKTK). The results provide the basis for the development of new leukemia treatments using specific inhibitors, which block growth signals.
Gene mutations often trigger cancer. These changes in the DNA mostly affect the regulators of cellular metabolism or cell growth, which cause cells to degenerate and proliferate rapidly. Many such gene mutations that cause leukemia have been identified.
In about one third of patients with acute myeloid leukemia (AML) the malignant cells have a mutation in the growth-regulating FLT3 receptor. As the team of scientists headed by Dr. Philipp Greif and Professor Karsten Spiekermann have now discovered, blood cancer cells from a substantial number of patients in a subgroup of AML (so-called core-binding factor leukemias) also carry mutations in this receptor. Mutations affecting amino-acid position N676 have not been previously detected and may allow a new classification of this form of leukemia, which is characterized by extremely high white blood cell counts. “The FLT3 receptor mutations we have found in these leukemia patients provide a new basis for treating the disease,” says Dr. Philipp Greif. “We already have FLT3 receptor inhibitors at hand, which we can now use to treat the affected patients.”
The study was conducted by the clinical cooperative group “Pathogenesis of acute myeloid leukemia”, a collaboration between the Helmholtz Zentrum München (HMGU) and the Department of Internal Medicine 3 at the Hospital of the Ludwig Maximilians University (LMU). The project leader and last author, Dr. Philipp Greif, heads a team of young scientists funded by the German Cancer Consortium (DKTK) within the clinical cooperative group. Professor Wolfgang Hiddemann, who heads the group, stresses the importance of this interdisciplinary collaboration: “Our results show in an exemplary way how innovative research methods, such as high-throughput DNA sequencing, allow discoveries, even in structures that have already been thoroughly examined. These insights into the molecular basis of the disease open up new treatment options for patients.”
Opatz, S. et al. (2013), Exome sequencing identifies recurring FLT3 N676K mutations in core-binding factor leukemia, Blood, doi: 10.1182/blood-2013-01-476473
Link to publication
As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,100 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 34,000 staff members. www.helmholtz-muenchen.de
With the establishment of clinical cooperation groups, the Helmholtz Zentrum München pursues an interdisciplinary approach to research in order to promote translational research, in other words to further develop basic science and make it directly usable for human subjects. Knowledge transfer between the laboratory and the patient’s bed is being realized through the close collaboration between scientists at the Helmholtz Zentrum München with clinicians at Munich universities as well as at the Städtisches Klinikum München (Munich Municipal Hospital).
The aim of the “Pathogenesis of acute myeloid leukemia” clinical cooperative group is to identify mutations that can cause leukemia and to establish model systems to examine whether or how a particular mutation can trigger the disease. This knowledge will ultimately lead to improvements in treatments for leukemia patients.
The project received a grant from the German Cancer Aid (Project 109031) as well as knock-on funding from the Collaborative Reseach Center “Molecular Mechanisms of Normal and Malignant Hematopoiesis” (CRC 684) supported by the German Research Foundation (DFG).
Specialist contact at Helmholtz Zentrum München
Dr. Philipp Greif, “Pathogenesis of acute myeloid leukemia” clinical cooperative group of Helmholtz Zentrum München and Hospital of the Ludwig Maximilians University, Munich, Marchioninistr. 15, 81377 München, Tel. +49 89 3187-1357