Characterization of Natural Killer Cells in Polycythemia verae and Acute Myeloid Leukemia
authors
keywords
- Natural Killer cells
- JAK2 tyrosine kinase
- Natural Cytotoxicity Receptors
document type
THESEabstract
In 2012, new cases of hematological malignancies in France have been estimated at 35,000. More than one third of cases are myeloid haemopathies. To date, the latest advances in blood disorders treatments lead to a better complete remission rate and a better survival rate after treatment. However, the risk of relapse remains high. Relapses are due to the proliferation of residual tumor cells that have resisted to the treatment. NK cells, which are involved in immune surveillance and which are naturally capable of killing tumor cells, should kill these residual cells, but many anomalies have been observed in most malignancies. Our project is included in the understanding of NK cells role in the development of these diseases. In a first part, we focused on polycythemia Vera (PV) for several reasons: the pathology has a slowly progressive disease, it can evolve into myelofibrosis or acute myelogenous leukemia, and it is characterized by the presence of JAK2 mutation (JAK2 V617F, exon 14, or, less frequently, involving exon 12) in myeloid lineage, for 95% of PV patients. We wanted to know if this mutation was found in NK cells from PV patients and what effects the mutation had on NK cells functions. Our results have shown that although the mutation was found in NK cells, it appears to have no impact on NK cells functions. We conclude that the evolution of PV to leukemia is not due to a loss of NK cell functions but to their inhibition by cellular environment. In a second part, we investigated the regulation of natural cytotoxicity receptors (NCR) in acute myeloid leukemia (AML) because previous works have shown that NCR are weakly expressed in AML patients, that this down-regulation is acquired during evolution of AML and reversible after complete remission, ant that NCR weak expression is related to poor prognosis. We supposed that the expression of the three NCR has a common regulation at genes transcription level. Our bioinformatic researches and our experiment of chromatin immunoprecipitation (Chip) show that ETS-1 transcription factor is a good candidate involved in the common regulation of the three NCR.
