Molekulární základy klonální heterogenity hematologických onemocnění

Babošová, Oľga

Tumor heterogeneity has been recognized for decades. The molecular mechanisms impacting clonal heterogeneity in hematological diseases, specifically myeloproliferative neoplasms (MPN) and mantle cell lymphoma, with the focus on several inherited genetic factors, inflammation, the protective mechanisms of DNA damage response (DDR) in the leukemic transformation and the treatment strategies are the focus of this thesis. Firstly, I focus on studying germline JAK2 variants and how these may influence the initiation and progression of MPN diseases, and even contribute to further genomic alterations in the mutated clone. A study performed by our cooperating lab in Utah, USA,1 analyzing the mutational landscape of 31 JAK2 V617F-positive polycythemia vera (PV) patients identified two novel germline mutations in JAK2 gene, JAK2 T108A and JAK2 L393V. Another study2 , performed by our cooperating lab in Olomouc, Czech Republic, characterized two germline JAK2 mutations, E846D and R1063H, in a case of hereditary erythrocytosis accompanied by megakaryocytic atypia. The JAK2 R1063H variant was initially described in 3 out of 93 PV patients that were JAK2 V617F-positive.3 Our aim was to identify the role of selected inherited mutations in JAK2 gene in the initiation and progression of myeloproliferative...

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