Clinical Cooperation Unit Molecular Hematology/Oncology

Numerical and structural chromosomal alterations and chromosomal instability are common features of human malignancies. In addition, intratumoral genetic heterogeneity and clonal evolution are major contributors to disease progression, relapse and treatment resistance. Despite the fact that chromosomal instability appears to be a major cause of tumor development and progression, little is known about its molecular origins. The Clinical Cooperation Unit Molecular Hematology/Oncology is studying the molecular mechanisms responsible for the induction of chromosomal instability and clonal evolution in malignant neoplasias with a special emphasis on acute myeloid leukemia, in which complex karyotype aberrations are associated with a particularly poor outcome. One research topic focuses on causes and consequences of amplified centrosomes – the spindle pole organizers responsible for correct chromosome segregation during mitosis – in human malignancies. Other current topics center around whole-genome sequencing approaches, aiming to identify mutations responsible for chromosomal instability in complex karyotype acute myeloid leukemias, as well as the identification of small molecule compounds that target aneuploidy and mutant enzymes, e.g. isocitrate dehydrogenase, in acute myeloid leukemia. As major contributions, the Department has shown that both chromosomal instability and clonal evolution are associated with disease progression and poor prognosis in myeloid malignancies. Mechanistically, novel components of the centrosome replication machinery have been identified, and mechanisms of normal centrosome replication and centrosome amplification in cancer cells have been elucidated. Whole-genome siRNA screening enabled the group to identify the mechanisms leading to clustering of supernumerary centrosomes into two functional spindle poles in cancer cells. Small molecule screening led to the identification of compounds that inhibit centrosomal clustering as a novel anticancer strategy. In addition, we have in close collaboration with the Department of Neuropathology, University of Heidelberg and Bayer Healthcare developed a compound that selectively inhibits mutant isocitrate dehydrogenase (IDH1) in both acute myeloid leukemia and gliomas, thereby enabling targeted treatment of these disorders.

FUTURE OUTLOOK
The aim of the Department’s research is to better understand the processes leading to chromosomal instability and, consequently, to tumor development and progression. A further goal is to exploit the results of this work in order to establish new methods of tumor classification and treatment.