Mutant JAK3 signaling is increased by loss of wild type JAK3 or by acquiring secondary JAK3 mutations in T-ALL

Sandrine Degryse, Simon Bornschein, Charles E. de Bock, Emilie Leroy, Marlies Vanden Bempt, Sofie Demeyer, Kris Jacobs, Ellen Geerdens, Olga Gielen, Jean Soulier, Christine J. Harrison, Stefan N. Constantinescu and Jan Cools

Key points

  • One third of T-ALL cases with JAK3 mutation harbor two JAK3 mutations.

  • Double JAK3 mutants show stronger signaling than single JAK3 mutants.


The JAK3 tyrosine kinase is mutated in 10 to 16% of T-cell acute lymphoblastic leukemia (T-ALL) cases. JAK3 mutants induce constitutive JAK/STAT signaling and cause leukemia when expressed in the bone marrow cells of mice. Surprisingly, we observed that one third of the JAK3 mutant T-ALL cases harbor two JAK3 mutations, some of which are mono-allelic and others that are bi-allelic. Our data suggest that wild type JAK3 competes with mutant JAK3(M511I) for binding to the common gamma chain and thereby suppresses its oncogenic potential. We demonstrate that JAK3(M511I) can increase its limited oncogenic potential through the acquisition of an additional mutation in the mutant JAK3 allele. These double JAK3 mutants show increased STAT5 activation, increased potential to transform primary mouse pro-T-cells to IL7 independent growth and were not affected by wild type JAK3 expression. These data extend our insight in the oncogenic properties of JAK3 mutations and provide an explanation why progression of JAK3 mutant T-ALL cases can be associated with the accumulation of additional JAK3 mutations.

  • Submitted July 20, 2017.
  • Accepted November 23, 2017.