Le rôle de la protéine JAK3 dans l'oncogenèse des hémopathies agressives à cellules NK

Nasal-type natural killer cell lymphoma (NKCL) represent a rare form of lymphoproliferative disease, characterized by its aggressiveness and its poor prognosis. In this work, we sought to better understand the pathophysiological mechanisms of this disease, with a view to identify original therapeutical targets. We identified the transcription factor STAT3 as an oncogene in NKCL. Subsequently, we investigated the mechanisms underlying the constitutive activation of STAT3. From the study of four NK cell lines, we could demonstrate the constitutive phosphorylation of STATs proteins, PI3K/Akt and MAPK/Erk pathways, which led us to identify a constitutive phosphorylation of JAK3 protein. This constitutive JAK3 phosphorylation renders NK cells hypersensitive to interleukin-2. We have shown that the constitutive phosphorylation of JAK3 is also found in primary biopsies of patients with NKCL, with a remarkably high frequency (88%). The sequencing of JAK3 gene in our four NK cell lines led us identifying a unique mutation in the JH2 domain (exon 13) (JAK3 A573V). No other mutation could be detected on the other 23 exons of the gene. Therefore, the A573V mutation frequency in NKCL is of 3/22 (14%). NKCL to date thus represent the hematological malignancy for which a mutation of JAK3 is most often observed. Our results establish for the first time a dysregulation of JAK3 protein in NKCL, which results in a hypersensitivity of these malignant cells for interleukin-2. The identification of a gain-of-function mutation in JAK3 reinforces the role of this protein family in oncology, and offers promising perspectives for original therapies that could specifically target JAK3.