Laboratory of advanced diagnostics and experimental haematology
Head: Vladimír Divoký
Olomouc node
HOME INSTITUTION
Faculty of Medicine PU in Olomouc
RESEARCH PROGRAMME(S)
RP 1 - Molecular basis of cancer and molecular targets
From molecular diagnostics to humanised models and back to personalised medicine.
- Mission: Unravel the molecular pathogenesis of congenital and acquired haematopoietic disorders, especially pre-leukaemic conditions and myeloid malignancies, and use research findings to develop new therapeutic approaches.
- Vision: Characterise molecular targets and design novel therapeutic strategies targeting leukaemogenesis.
The frame of our research is based on our earlier contributions to the understanding of cooperation between oncogene-induced DNA-damage response (DDR) and inflammatory cytokine network in leukaemogenesis. We described DDR as a critical mechanism rate-limiting for malignant transformation by the haematopoietic oncogene, synergizing with inflammatory factors in checkpoint signalling and senescence, thereby counteracting leukaemogenesis. In the case of myeloproliferative neoplasias (MPN), we elaborated on a concept of protection mechanisms that guard myeloproliferative progenitors from cell-intrinsic and cell-extrinsic DNA damage and thus DDR, facilitating creation of a barrier preventing cell cycle arrest, myelofibrosis and rapid malignant transformation. Currently, we test whether and how these processes can be targeted in preventing full leukaemia transformation from different pre-leukaemia disease states.
SELECTED PUBLICATIONS
- Takacova S, Slany R, Bartkova J, Stranecky V, Dolezel P, Luzna P, Bartek J, Divoky V. DNA damage response and inflammatory signaling limit the MLL-ENL-induced leukemogenesis in vivo. Cancer Cell. 2012 Apr 17;21(4):517-31. DOI: 10.1016/j.ccr.2012.01.021
- Kapralova K, Horvathova M, Pecquet C, Fialova Kucerova J, Pospisilova D, Leroy E, Kralova B, Milosevic Feenstra JD, Schischlik F, Kralovics R, Constantinescu SN, Divoky V. Cooperation of germ line JAK2 mutations E846D and R1063H in hereditary erythrocytosis with megakaryocytic atypia. Blood. 2016;128(10):1418-23. DOI: 10.1182/blood-2016-02-698951
- Gucky T, Reznickova E, Radosova Muchova T, Jorda R, Klejova Z, Malinkova V, Berka K, Bazgier V, Ajani H, Lepsik M, Divoky V, Krystof V. Discovery of N2-(4-Amino-cyclohexyl)-9-cyclopentyl- N6-(4-morpholin-4-ylmethyl-phenyl)- 9H-purine-2,6-diamine as a Potent FLT3 Kinase Inhibitor for Acute Myeloid Leukemia with FLT3 Mutations. J Med Chem. 2018;61(9):3855-3869. DOI: 10.1021/acs.jmedchem.7b01529
- Stetka J; Vyhlidalova P, Lanikova L, Koralkova P, Gursky J, Hlusi A, Flodr P, Hubackova S, Bartek J, Hodny Z, Divoky V. Addiction to DUSP1 protects JAK2V617F-driven polycythemia vera progenitors against inflammatory stress and DNA damage, allowing chronic proliferation. Oncogene. 2019;38(28):5627-5642. DOI: 10.1038/s41388-019-0813-7
- Kapralova K, Jahoda O, Koralkova P, Gursky J, Lanikova L, Pospisilova D, Divoky V, Horvathova M. Oxidative DNA Damage, Inflammatory Signature, and Altered Erythrocytes Properties in Diamond-Blackfan Anemia. Int J Mol Sci. 2020;21(24):9652. DOI: 10.3390/ijms21249652
COLLABORATION WITHIN THE NICR
SPECIALIZED EXPERTISE AND TECHNOLOGY
Humanised mouse and cellular models of haematological diseases
Functional analysis of human haematopoietic progenitors for diagnosis and research
Advanced molecular and cell biology methods
COLLABORATION WITH LARGE RESEARCH INFRASTRUCTURES AND RESEARCH CENTRES
European Reference Network (ERN) on Rare Haematological Diseases ERN-EuroBloodNet
European Network for Rare and Congenital Anaemias ENERCA
Biotechnology and Biomedicine Centre of the Czech Academy of Sciences and the Charles University BIOCEV
Central European Institute of Technology at Masaryk University CEITEC MU
Czech Centre for Phenogenomics CCP