We recently showed that most JAK3 mutations, identified in T-ALL patient samples,
caused leukemia in a mouse model 8]. In the development of mouse models expressing JAK3 mutations, we mainly focused
on the JAK3 M511I mutation, which is the most common mutation found in T-ALL. Mice
receiving bone marrow transplantation with cells expressing the JAK3 M511I mutant
developed a lymphoproliferative disease over the first 12Â weeks, followed by progression
to an acute phase characterized by a rapid increase in white blood cell (WBC) counts.
All animals eventually succumbed to the disease within 14 to 28Â weeks after receiving
the bone marrow transplantation 8]. The disease was characterized by splenomegaly, enlarged thymus, and enlarged lymph
nodes. All mice showed an accumulation of CD8 single positive immature T cells in
the peripheral blood and hematopoietic tissues. The leukemic cells were transplantable
to secondary recipient mice and were characterized by the presence of additional mutations
in Notch1, Pten, Kras, and other genes. Mice which received a bone marrow transplant
of cells expressing wild-type JAK3 did not develop any disease phenotype 8].
Primary and secondary transplanted mice were subsequently used to test the efficacy
of the JAK3-selective inhibitor, tofacitinib (Xeljanz, Pfizer), to treat leukemia
progression. Mice treated with tofacitinib showed a decrease in WBC count, while mice
receiving placebo treatment had an increase in WBC count during treatment. Pathological
analysis of tissues showed a high percentage of apoptotic cells in tofacitinib-treated
mice, while placebo-treated mice had very low amount of apoptotic cells. Spleen and
thymus weight was significantly lower in tofacitinib-treated mice compared to placebo-treated
mice. These data demonstrate that JAK inhibitors such as tofacitinib show activity
in mouse leukemia models 8]. However, when treatment was stopped, WBC counts increased, and all animals eventually
succumbed to the disease, showing that kinase inhibitors alone cannot lead to complete
eradication of the leukemia cells in this mouse model.
In a separate study, Maude and colleagues investigated the efficacy of ruxolitinib
for the treatment of early T cell precursor ALL (ETP-ALL) using xenografted human
leukemia samples. Injection of ETP-ALL samples in immune deficient NSG mice led to
the expansion of the leukemia cells in vivo, which was observed by increasing numbers
of human blast cells in the peripheral blood and spleen of the NSG mice over time.
Treatment of these animals with ruxolitinib, a JAK1/JAK2 inhibitor, caused a dramatic
reduction of peripheral and spleen blasts, even as a single agent. Interestingly,
the efficacy of ruxolitinib was observed not only in three samples with JAK1 or JAK3
mutation, but also in two ETP-ALL samples without JAK1, JAK3, or IL7R mutation 10]. These data indicate that JAK inhibitors are promising agents for the treatment of
T-ALL, and that clinical trials to test these agents are warranted. JAK1, JAK3, or
IL7R mutations predict response to JAK inhibitors, but even T-ALL cases without such
mutations could potentially respond to JAK inhibition, most likely due to the presence
of other, yet unknown, mechanisms leading to activation of the JAK/STAT pathway.