Genetic Basis of Hematological Malignancies
Robert Kralovics, Ph.D.
CeMM Laboratories

The laboratory is involved in identification of chromosomal aberrations in patients with chronic and acute hematological malignancies. The objective of these studies is to find somatic mutations that initiate the clonal expansion of hematopoietic stem cells and device therapeutic interventions that can prevent the clonal evolution of these cells leading to more severe phenotypes.

Chronic myeloid malignancies

Genetic basis of excessive production of differentiated blood cells has been the primary focus of the laboratory with a particular interest in myeloproliferative disorders (MPD). MPD represents a heterogeneous group of diseases characterized by excessive production of erythroid, myeloid, and megakaryocytic cells. Using genetic analysis, we have identified a gain-of-function mutation (V617F) in the JAK2 gene in about 50% of patients with MPD. One of the objectives of the laboratory is to determine the pathogenetic role of the JAK2 mutation in MPD and other hematological malignancies. At present, it is clear that JAK2-V617F acts in collaboration with other mutations and chromosomal aberrations in the development of MPD phenotype. The laboratory participates in clinical research studying the role of JAK2-V617F in disease progression, therapeutic outcome, etc. Another objective of the laboratory is to identify somatic mutations associated with JAK2-V617F negative MPD and post-MPD acute myeloid leukemia as well as chronic myeloid leukemia and myelodysplastic syndrome.

Familial hematological disorders

Familial predispositions to hematological malignancies provide a unique opportunity to identify relevant genes by employing linkage analysis and positional cloning. The laboratory initiated studies of familial MPD, CLL, and AML but studies of familial MPD has been in the center of attention of the laboratory. The laboratory is continuously searching for patients with a family history of hematological malignancies and is open for collaboration with hematologists or primary practitioners worldwide who identified such families.

Selected references

Harutyunyan A, Klampfl T, Cazzola M, Kralovics R (2011) p53 lesions in leukemic transformation. N Engl J Med 364, 488-490.

Olcaydu D, Rumi E, Harutyunyan A, Passamonti F, Pietra D, Pascutto C, Berg T, Jäger R, Hammond E, Cazzola M, Kralovics R (2011) The role of the JAK2 GGCC haplotype and the TET2 gene in familial myeloproliferative disorders. Haematologica 96: 367-374.

Jäger R, Gisslinger H, Passamonti F, Rumi E, Berg T, Gisslinger B, Pietra D, Harutyunyan A, Klampfl T, Olcaydu D, Cazzola M, Kralovics R (2010) Deletions of the transcription factor Ikaros in myeloproliferative neoplasms. Leukemia 24: 1290-1298.

Olcaydu D, Harutyunyan A, Jager R, Berg T, Gisslinger B, Pabinger I, Gisslinger H, Kralovics R (2009) A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat Genet 41: 450-454.

Kralovics R. (2008) Genetic complexity of myeloproliferative neoplasms. Leukemia 22, 1841-1848.

Kralovics R, Teo SS, Li S, Theocharides A, Buser AS, Skoda RC. (2006) Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders. Blood 108, 1377-1380.



Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC. (2005) A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 352, 1779-1790.



Kralovics R, Stockton DW, Prchal JT. (2003) Clonal hematopoiesis in familial polycythemia vera suggests the involvement of multiple mutational events in the early pathogenesis of the disease. Blood 102, 3793-3796.



Kralovics R, Guan Y, Prchal JT. (2002) Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera. Experimental Hematology 30, 229-236.