This work concerns malignant myeloid hemopathies called classical BCR-ABL-negative Myeloproliferative Neoplasms (MPN) and include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). They result from the transformation of a multipotent hematopoietic stem cell (HSC) with hyperproliferation but no blockade of differentiation. The most common molecular defect is the acquired point mutation JAK2V617F resulting into the activation of the cytokine receptor/JAK2 pathway. We have developed a mouse constitutive and a conditional JAK2V617F knock-in (KI) mouse models. These animals developed a disease mimicking human PV evolving into secondary MF. They also displayed an age dependent increase in the total numbers of early hematopoietic cells (phenotype LK, LSK and SLAM: LSK/CD48-/CD150+). Using In vivo competitive repopulation assays we demonstrated that cells from KI origin outcompeted their WT counterparts and that a low number of JAK2V617F KI SLAM cells propagates the disease. These results show that the sole JAK2V617F mutation, without any additional mutations, is sufficient for disease phenotype and emergence. Using this KI mouse model, we tested the effect of interferon-a (IFNa) treatment on MPN development. We found that IFNa treats the disease phenotype by blocking the propagation of early JAK2V617F cells and eradicates disease-initiating cells, showing that IFNα could cure the disease in mice, as shown in some PV patients. Finally, we developed a new method combining the measurement of 46/1 SNPs and JAK2V617F allele burdens in blood predicting the frequency of normal, heterozygous and homozygous JAK2V617F clones in PV patients. This study suggested that IFNa preferentially targets the homozygous JAK2V617F clone in PV patients suggesting a link between the levels of JAK2 signaling and the success of the IFNa response.
| Identifer | oai:union.ndltd.org:CCSD/oai:tel.archives-ouvertes.fr:tel-00918966 |
| Date | 27 November 2013 |
| Creators | Hasan, Salma |
| Publisher | Université Paris Sud - Paris XI |
| Source Sets | CCSD theses-EN-ligne, France |
| Language | English |
| Detected Language | English |
| Type | PhD thesis |
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