Genetics of hematological disorders
Medical University of Vienna
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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 has been Principal Investigator at CeMM since 2006 and a Group Leader at the Medical University of Vienna (MedUni Vienna) since 2017. He earned his master’s degree in Molecular Biology and Genetics at Comenius University and his PhD in Genomics at the Institute of Biophysics of the Academy of Sciences of the Czech Republic. His postdoctoral work was based on the genetics of myeloproliferative disorders working with Josef Prchal at the University of Alabama in Birmingham, USA. In 2000, Robert joined Prchal’s group as Assistant Professor at Baylor College of Medicine in Houston. In 2001, he became project leader with Radek Skoda in Basel. Kralovics’ research interests are primarily in myeloproliferative neoplasms (MPNs) and in myeloid malignancies in general. His major achievements so far have been the identification of disease-causing mutations in the JAK2 kinase gene (V617F) in 2005 and in the calreticulin gene (CALR) in 2013. Using advanced genomic approaches, Robert Kralovics continues his research at CeMM and MedUni Vienna to identify new therapeutic strategies for MPN. His aim is to understand how genetic variability contributes to MPN and how it could be treated in a personalized manner.
Schischlik F, Jäger R, Rosebrock F, Hug E, Schuster M, Holly R, Fuchs E, Milosevic Feenstra JD, Bogner E, Gisslinger B, Schalling M, Rumi E, Pietra D, Fischer G, Faé I, Vulliard L, Menche J, Haferlach T, Meggendorfer M, Stengel A, Bock C, Cazzola M, Gisslinger H, Kralovics R. Mutational landscape of the transcriptome offers putative targets for immunotherapy of myeloproliferative neoplasms. Blood. 2019 Jul 11;134(2):199-210. (abstract)
Nivarthi H, Chen D, Cleary C, Kubesova B, Jäger R, Bogner E, Marty C, Pecquet C, Vainchenker W, Constantinescu SN, Kralovics R. Thrombopoietin receptor is required for the oncogenic function of CALR mutants. Leukemia. 2016 Aug;30(8):1759-63. (abstract)
Milosevic Feenstra JD, Nivarthi H, Gisslinger H, Leroy E, Rumi E, Chachoua I, Bagienski K, Kubesova B, Pietra D, Gisslinger B, Milanesi C, Jäger R, Chen D, Berg T, Schalling M, Schuster M, Bock C, Constantinescu SN, Cazzola M, Kralovics R. Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms. Blood. 2016 Jan 21;127(3):325-32. (abstract)
Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, Them NC, Berg T, Gisslinger B, Pietra D, Chen D, Vladimer GI, Bagienski K, Milanesi C, Casetti IC, Sant'Antonio E, Ferretti V, Elena C, Schischlik F, Cleary C, Six M, Schalling M, Schönegger A, Bock C, Malcovati L, Pascutto C, Superti-Furga G, Cazzola M, Kralovics R. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013 Dec 19;369(25):2379-90. (abstract)
Milosevic JD, Puda A, Malcovati L, Berg T, Hofbauer M, Stukalov A, Klampfl T, Harutyunyan AS, Gisslinger H, Gisslinger B, Burjanivova T, Rumi E, Pietra D, Elena C, Vannucchi AM, Doubek M, Dvorakova D, Robesova B, Wieser R, Koller E, Suvajdzic N, Tomin D, Tosic N, Colinge J, Racil Z, Steurer M, Pavlovic S, Cazzola M, Kralovics R. Clinical significance of genetic aberrations in secondary acute myeloid leukemia. Am J Hematol. 2012 Nov;87(11):1010-6. (abstract)
Klampfl T, Harutyunyan A, Berg T, Gisslinger B, Schalling M, Bagienski K, Olcaydu D, Passamonti F, Rumi E, Pietra D, Jäger R, Pieri L, Guglielmelli P, Iacobucci I, Martinelli G, Cazzola M, Vannucchi AM, Gisslinger H, Kralovics R. Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression. Blood. 2011 Jul 7;118(1):167-76. (abstract)
Harutyunyan A, Klampfl T, Cazzola M, Kralovics R. p53 lesions in leukemic transformation. N Engl J Med. 2011 Feb 3;364(5):488-90. (abstract)
Olcaydu D, Harutyunyan A, Jäger R, Berg T, Gisslinger B, Pabinger I, Gisslinger H, Kralovics R. A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat Genet. 2009 Apr;41(4):450-4.(abstract)
Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005 Apr 28;352(17):1779-90. (abstract)