Effects of p38α/β inhibition on acute lymphoblastic leukemia proliferation and survival in vivo

P38 alpha/beta has been described as a tumor-suppressor controlling cell cycle checkpoints and senescence in epithelial malignancies. However, P38 alpha/beta also regulates other cellular processes. Here, we describe a role of P38 alpha/beta as a regulator of acute lymphoblastic leukemia (ALL) proliferation and survival in experimental ALL models. We also report first evidence that P38 alpha/beta phosphorylation is associated with the occurrence of relapses in TEL-AML1-positive leukemia. First, in vitro experiments show that P38 alpha/beta signaling is induced in a cyclical manner upon initiation of proliferation and remains activated during log-phase of cell growth. Next, we provide evidence that growth-permissive signals in the bone marrow activate P38 alpha/beta in a novel avian ALL model, in which therapeutic targeting can be tested. We further demonstrate that P38 alpha/beta inhibition by small molecules can suppress leukemic expansion and prolong survival of mice bearing ALL cell lines and primary cells. Knockdown of p38 alpha strongly delays leukemogenesis in mice xenografted with cell lines. Finally, we show that in xenografted TEL-AML1 patients, ex vivo P38 alpha/beta phosphorylation is associated with an inferior long-term relapse-free survival. We propose P38 alpha/beta as a mediator of proliferation and survival in ALL and show first preclinical evidence for P38 alpha/beta inhibition as an adjunct approach to conventional therapies.