The team is working on the pathogenesis of Polycythemia Vera (PV) and other BCR-ABL negative myeloproliferative neoplasms.
The classical BCR-ABL negative myeloproliferative neoplasms have for biological hallmark a hypersensitivity to cytokine, especially erythropoietin, which explains the increased erythrocyte production and the polycythemia. All the mutations discovered responsible for the phenotype (driver mutations) concern the cytokine receptor/ JAK2 pathway. The most frequent somatic mutation is the JAK2V617F (exon 14), which is present in 95% of PV, 60% of essential thrombocythemia (ET) and 50% of primary myelofibrosis (PMF). The other mutations concern JAK2 itself, especially with mutations in the Exon 12 in 3% of PV; MPL, the thrombopoietin receptor in the W515 codon in 8-10% of PMF and 3% of ET and rare loss of function mutations in LNK (SH2B3) that negatively regulates the JAK2 activity or CBL (Casitas B-cell lymphoma) protein with a ubiquitin ligase activity which targets JAK2, STAT5 and MPL.
Although many progresses have been made from 2005 with the discovery of the JAK2V617F both in the pathogenesis of these disorders and their treatment (development of JAK2 inhibitors), four main questions remain to be solved concerning the pathogenesis of these disorders.
What are the other mutations responsible for the phenotype of the JAK2 and MPL negative ET and PMF?
Are mutations in the signaling pathways sufficient to induce a clonal clinical disorder or do they need the requirement of other genetic events? They are already strong evidence that in less than 20% of ET and PV, another genetic event is present such as mutations of TET2 or an epigenetic regulator or mutations in a gene of splicing. However one or several other mutations are present in PMF. These mutations may be involved in two functions: i) clonal dominance as for TET2 mutations and ii) induction of myelodysplatic features as observed in PMF, as for the ASXL1 and SRSF2 mutations.
The myeloproliferative neoplasms are usually sporadic but in up to 8% there is a familial prevalence. This predisposition can be related to some SNPs such as the 46/1 haplotype in JAK2 or a recent SNP in MYB, but this leads to an increase risk of MPN of about 2 to 5-fold. In parallel there are families with a true mendelian transmission of the MPN. In this case, in most families, acquired mutations in the same genes as in sporadic cases are responsible of the MPN in the adult life. However, there is no germline transmission of these mutants, maybe with the exception of TET2 mutations. Thus a main question remains what are the genetic events responsible for this predisposition.
The main driver mutation is JAK2V617F, a gain of function mutation in the pseudokinase domain of JAK2. It remains to be understood how this mutation acts (is it a simple constitutive signaling via cytokine receptors or JAK2V617F interacts with new molecules and pathways), how it induces several phenotypes (associated mutations or copy number through a LOH), how it acts on hematopoietic stem cells and how it induces a genetic instability. These precise answers may help in the future for the development of new therapies.
Our group tries to answer to these different questions by:
- Modeling the disease in the mouse through inducible jak2V617F mice and tet2 knockout mice and the development of iPS from patients with JAK2V617F and TET2 mutations as with presumptive predisposition genes.
- Studying the hematopoiesis of patients both in sporadic and familial forms.
- Searching new genetic alterations in sporadic and familial forms through genome wide techniques including NGS.