Gerhard Ehninger - Bone marrow transplantation

Previous and current research

Molecular pathogenesis and novel treatment strategies in acute myeloid leukemia (AML)

Acute myeloid leukemia (AML) represents a heterogeneous group of early stem cell disorders, which are characterized by an uncontrolled expansion of malignant cells which are blocked at certain stages of myeloid differentiation. Several different genetic defects have been described, including translocations involving genes of the CBF family as well activating mutations in signal transduction proteins, e.g. members of the Ras family of small G-proteins (N-RAS, K-RAS) and receptor tyrosine kinases (RTKs). A major focus of our group is the analysis of the molecular pathogenesis and novel prognostic factors in adult patients with AML (1;2). More recently, we have focused on activating mutations of the FLT3-RTK, since this alterations has been found to represent the single most common genetic aberration, present in up to 35% of adolescent and adult patients with AML. The alterations comprise short internal tandem duplication (ITD) mutations located in the regulatory juxtamembrane region (JM) as well as point mutations in the second tyrosine kinase domain (TKD). These mutations induce factor independent activation of FLT3 and induce downstream targets including STAT5 and RAS. FLT3 mutations are more common in patients with normal karyotype and appear to be associated with a higher rate of relapse after conventional chemotherapy. We have investigated the prevalence of this mutation in large cohort of almost 1000 patients with AML (3). We also investigated potentially cooperating mutations, e.g. partial tandem duplications (PTD) of the MLL gene (4). Another focus was the differential sensitivity of different mutations towards inhibition with specific tyrosine kinase inhibitors (5). We further found that in about 15% of patients with FLT3-ITD mutations, loss of the wt-FLT3 allele can be observed, and these patients have a particularly poor outcome, with a median disease free survival between 4 and 6 months. The pathogenetic background of this additional alteration is completely unknown, but it is speculated that the mutant-FLT3 receptor homodimers in patients with loss of wt-FLT3 have a stronger transforming capacity compared to mut/wt heterodimers. We have started to evaluate this question in more detail using cotransfection experiments of wt and mutant FLT3 together with the group of Dr. Justus Duyster, TU Munich. First experiments in mouse cells (Ba/F3, 32D) do not support the initial hypothesis.

Future prospects and goals

Selected publications

Mohr, B., Bornhauser, M., Thiede, C., Schakel, U., Schaich, M., Illmer, T., Pascheberg, U. and Ehninger, G. (2000): Comparison of spectral karyotyping and conventional cytogenetics in 39 patients with acute myeloid leukemia and myelodysplastic syndrome. Leukemia, 14:1031-1038

Illmer, T., Schuler, U. S, Thiede, C., Schwarz, U. I., Kim, R. B, Gotthard S., Freund, D., Schakel, U., Ehninger, G. and Schaich, M. (2002): MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients. Cancer Res, 62:4955-4962

Thiede, C., Steudel, C., Mohr, B., Schaich, M., Schakel, U., Platzbecker, U., Wermke, M., Bornhauser, M., Ritter, M., Neubauer, A., Ehninger, G. and Illmer, T. (2002): Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99:4326-4335

Steudel, C., Wermke, M., Schaich, M., Schakel, U., Illmer, T., Ehninger, G. and Thiede, C. (2003): Comparative analysis of MLL partial tandem duplication and FLT3 internal tandem duplication mutations in 956 adult patients with acute myeloid leukemia. Genes Chromosomes Cancer, 37:237-251

Gerhard Ehninger

1978-1985: Internship and residency at the Clinic of Internal Medicine, University Tübingen

1985-1991: Senior physician at the Clinic of Internal Medicine in Tübingen, Department II

1991: Associate professor

1994: Director (Medizinische Klinik I, Universitätsklinikum, Dresden)