Poster Presentation 30th Lorne Cancer Conference 2018

A Knock-In model for JAK3A572V activating mutation reveals its intimate link to T cell hematopoietic disorders in vivo (#215)

Paola Rivera-Munoz 1 , Anouchka Laurent 1 , Aurelie Siret 1 , Cathy Ignacimouttou 1 , Melanie Cornejo 2 , Gary Gilliland 2 , Thomas Mercher 1 , Sebastien Malinge 1 3
  1. U1170 - Normal and pathologic hematopoiesis, INSERM - Gustave Roussy Institute, Villejuif, 75, France
  2. Division of Hematology, Brigham and Women’s Hospital - Harvard Medical School, Boston, MA, USA
  3. Telethon Kids Institute - Cancer Center, Subiaco, WA, Australia

JAK3 activating mutations are commonly seen in hematological malignancies affecting the myeloid, megakaryocytic, lymphoid and natural killer cell lineages. Among the hotspots found in the human JAK3 gene, the substitution of the two Alanine 572/573 to Valine is found in all types of hematopoietic disorders. Overexpressing models of several mutants JAK3, including the A572V substitution, highlighted the role of this constitutively activated mutants in the T cell lineage but to date, the functional impact of JAK3 mutations at an endogenous level remain unknown. Here, we developed a JAK3-A572V knock-in murine model and revealed that activated JAK3 leads to a progressive expansion of Cd8+ T cells in the periphery prior to colonize bone marrow, strongly resembling Cutaneous T cell lymphoma (CTCL). This phenotype is dose dependant since heterozygous mice will display the same phenotype with a longer latency. We also showed that these disorders are transplantable, phenotypically heterogeneous and cooperate with additional genetic alterations. Indeed, we revealed that activated mutant JAK3-A572V functionally cooperated with partial trisomy 21 to worsen the CTCL phenotype in vivo, and may lead to T-ALL showing Notch1 activation, at least in part through trisomy of the Ets2 gene. Finally, we assessed the efficacy of JAK3 inhibition in vitro and showed that both CTCL and T-ALL JAK3A572V T cells are sensitive to Tofacitinib treatment. In conclusion, we described here the first knock-In model of JAK3-A572V activating mutation and revealed that this model could be a useful tool to assess the efficacy of JAK3 inhibitors in T cell malignancies.