Poster Board I-963
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive and incurable cancer caused by infection from a retrovirus, Human T-cell Leukemia Virus type-1 (HTLV-1). HTLV-1 infects T cells and induces cell transformation through the expression of viral oncogenes such as tax. In newly infected cells, tax activates the expression of Interleukin-2 and the alpha subunit of its receptor (IL2RA) resulting in autocrine signaling that drives proliferation. In ATLL cells, tax is frequently deleted or silenced by methylation but there is constitutive activation of pathways downstream of IL-2 and related cytokines. These data led us to hypothesize that somatic mutations in this cytokine pathway may play a role in ATLL tumor progression. Encouraged by the recent discovery of activating mutations in JAK3 in diverse hematologic malignancies, we sequenced the exons of JAK3 in a small cohort of ATLL patients and found three missense mutations in the amino terminal FERM domain which were not found in Single Nucleotide Polymorphism databases. IL-2 signaling recapitulated in Human Embryonic Kidney 293T cells showed that these missense mutations caused increased tyrosine phosphorylation of the JAK3 substrate, STAT5A. Furthermore, enforced expression of these mutant JAK3s caused cytokine independent growth of BaF3 cells. The FERM domain of JAK3 is similar to the FERM domain of Focal Adhesion Kinase (FAK), which has a solved crystal structure. Interestingly, the FAK FERM domain contacts and autoinhibits its own kinase domain. Our homology-based model suggests that the JAK3 missense mutations disrupt the secondary structure needed for this intramolecular contact thereby perturbing autoregulation of JAK3 kinase activity. Our findings suggest that JAK3 gain of function may play an important role in ATLL disease progression.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.