CeMM Principal Investigator
Genetics of Hematological Disorders
Myeloid malignancies belong to a family of clonal, stem cell derived disorders of hematopoiesis. Stem cell clonality is initiated by mutations such as translocations or inversions in chromosomes, deletions and amplifications of genomic regions, or point mutations in a single gene. Most of these mutations will be passenger mutations but some might provide a selective advantage to the stem cell clone. These driver mutations are responsible for clonal expansion of a mutated clone, often giving it a competitive advantage over healthy cells in the bone marrow environment. Our research group aims to identify genomic aberrations in myeloid malignancies that initiate the clonal expansion of hematopoietic stem cells as well as mutations that cause familial predisposition to hematological malignancies. We use next generation sequencing of patient samples to identify these mutations, and other genetic factors that can contribute to cancer progression, which may aid early diagnosis and personalized therapies. Additionally, we aim to identify and investigate therapeutic interventions that may prevent the clonal evolution and disease progression.
High-resolution genomic analysis of leukemia
During cancer cell division mutations accumulate and are passed to the next generation of cancer cells. Although the vast majority of these newly acquired genomic mutations do not provide any benefit to the cancer clone, some lesions provide a selective advantage, which shapes the cancer genome in a given environment. We study the genomic architecture of leukemic cells in patients diagnosed with different forms of leukemia. In each patient, the leukemic genome is evaluated using Genome-Wide Human SNP 6.0 Array to detect large genomic aberrations and next-generation sequencing technologies to gain an extended view of the mutational status. Using this high-resolution genomic analysis approach, we will gain insights into both the initiation and the progression of the disease.
CALR mutations in MPN
We have recently identified novel mutations in the gene CALR in MPN patients. However, the mechanism by which these mutations can promote MPN development remains unknown. In order to investigate this further, we are using a variety of cell lines and generating mouse models that express the mutant proteins. These mouse models may enable us to gain a deeper insight into the biology behind these mutations, allowing us to further understand the MPN pathogenesis. These studies may contribute to the development of novel therapeutic regimes for MPN patients affected by these specific mutations.
Robert Kralovics completed his PhD in Biophysics at the Czech Academy of Sciences and was a postdoctoral fellow at the University of Alabama at Birmingham. He became Assistant Professor at Baylor College of Medicine, Houston, and following a project leader position at University Hospital Basel he joined CeMM in 2006.
Klampfl T, et al. (2013). Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 369, 2379-2390. (abstract)
Klampfl T, et al. (2011). Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression. Blood 118, 167-176. (abstract)
Milosevic JD, et al. (2012). Clinical significance of genetic aberrations in secondary acute myeloid leukemia. Am J Hematol 87, 1010-1016. (abstract)