A5021071087- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Acute Myeloid Leukemia Research
- Chronic Myeloid Leukemia Treatments
- Cytokine Signaling Pathways and Interactions
- Eosinophilic Disorders and Syndromes
- Kruppel-like factors research
- Histone Deacetylase Inhibitors Research
- Hemoglobinopathies and Related Disorders
- RNA Interference and Gene Delivery
- Drug Transport and Resistance Mechanisms
- Epigenetics and DNA Methylation
- Adenosine and Purinergic Signaling
University Hospital of Basel
2020-2025
University of Basel
2020-2025
Palacký University Olomouc
2015-2024
Slovak Academy of Sciences
2014
Abstract Pegylated interferon alfa (pegIFN-α) can induce molecular remissions in patients with JAK2-V617F–positive myeloproliferative neoplasms (MPNs) by targeting long-term hematopoietic stem cells (LT-HSCs). Additional somatic mutations genes regulating LT-HSC self-renewal, such as DNMT3A, have been reported to poorer responses pegIFN-α. We investigated whether DNMT3A loss leads alterations JAK2-V617F functions conferring resistance pegIFN-α treatment a mouse model of MPN and progenitors...
Inflammatory and oncogenic signaling converge in disease evolution of BCR–ABL-negative myeloproliferative neoplasms, clonal hematopoietic stem cell disorders characterized by gain-of-function mutation JAK2 kinase (JAK2V617F), with highest prevalence patients polycythemia vera (PV). Despite the high risk, DNA-damaging inflammatory microenvironment, PV progenitors tend to preserve their genomic stability over decades until progression post-PV myelofibrosis/acute myeloid leukemia. Using induced...
Hyperproliferation of myeloid and erythroid cells in myeloproliferative neoplasms (MPN) driven by the JAK2-V617F mutation is associated with altered metabolism. Given central role glutamine anabolic catabolic pathways, we examined effects pharmacologically inhibiting glutaminolysis, that is, conversion (Gln) to glutamate (Glu), using CB-839, a small molecular inhibitor enzyme glutaminase (GLS). We show CB-839 strongly reduced mitochondrial respiration rate bone marrow from mutant (VF) mice,...
Myeloproliferative neoplasms (MPNs) are caused by a somatic gain-of-function mutation in 1 of the 3 disease driver genes
JAK2-V617F mutation causes myeloproliferative neoplasms (MPN) that can manifest as polycythemia vera (PV), essential thrombocythemia (ET) or primary myelofibrosis (PMF). PV patients at diagnosis already exhibited iron deficiency, whereas ET had normal stores. We examined the influence of availability on MPN phenotype in mice expressing and JAK2 with a N542-E543del exon 12 (E12). At baseline control diet, all JAK2-mutant mouse models PV-like displayed although E12 maintained more for...
The development of the most common multidrug resistance (MDR) phenotype is associated with a massive overexpression P-glycoprotein (P-gp) in neoplastic cells.In current study, we used three L1210 cell variants: S cells -parental drugsensitive cells; R -drug-resistant P-gp due to selection vincristine; T stable transfection pHaMDRwt plasmid, which encodes human full-length P-gp.Several authors have described induction expression/activity malignant lines after treatment all-trans retinoic acid...
Abstract Myeloproliferative neoplasms (MPNs) are caused by a somatic gain-of-function mutation in one of three “disease driver” genes JAK2, MPL or CALR . About half MPN patients also carry additional mutations that modify the clinical course. The order acquisition these gene has been proposed to influence phenotype and evolution disease. We studied 50 JAK2 -V617F-positive who carried at least determined clonal architecture their hematopoiesis sequencing DNA from single cell derived colonies....
To better understand the molecular basis of resistance to azacitidine (AZA) therapy in myelodysplastic syndromes (MDS) and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), we performed RNA sequencing on pre-treatment CD34+ hematopoietic stem/progenitor cells (HSPCs) isolated from 25 MDS/AML-MRC patients discovery cohort (10 AZA responders (RD), six stable disease, nine progressive disease (PD) during therapy) eight controls. Eleven samples were also available for...