Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and 15%
of the treated patients suffer from relapse. Understanding the biological factors
that enhance or inhibit ALL cell proliferation can help in improving the current therapies.
During normal hematopoiesis, the MAPK family member p38 mediates growth-inhibitory
signals. In this study we have further investigated the role of p38 in ALL biology
in vitro and in vivo and found that it plays a pivotal role in ALL proliferation. The growth-kinetics
of several ALL cell lines were measured and were correlated with the phosphorylation
levels of p38. Most ALL cell lines exhibited a high phosphorylation level of p38 during
the log-phase of cell growth. Inhibition of p38, using either SB203580 or BIRB-796,
resulted in reduced proliferation of the cells. In addition, ALL cell lines or pediatric
ALL primary cells were xenografted into an avian or an NSG-mouse model. The animals
were treated with p38-inhibitors. Survival of the animals correlated inversely with
the activation of p38. Similar findings were observed in vivo when the cells were transduced with a p38-specific shRNA. Altogether, our data show
that p38α/β has a growth-stimulatory role in ALL, and that inhibition of this pathway
by small molecule inhibitors or via knock-down approaches suppresses engraftment and
prolongs survival of leukemic NSG mice. Accordingly, inhibiting the p38α/β pathway
could be used as an adjunct approach in ALL therapy.
