Ras activation in normal white blood cells and childhood acute lymphoblastic leukemia

Ras is an important cellular switch, relaying growth-promoting signals from the plasma membrane to the nucleus. In cultured cells, Ras is activated by various hematopoietic cytokines and growth factors, but the activation sta te of Ras in peripheral WBCs and bone marrow cells has not been studied nor has Ras activation been assessed in cells from patients with acute lymphob lastic leukemia (ALL). Using an enzyme-based method, we assessed Ras activa tion in peripheral WBCs, lymphocytes, and bone marrow cells from normal sub jects and from children with T-cell ALL (T-ALL) and B-Lineage ALL (B-ALL), In normal subjects, we found mean Ras activations of 14.3, 12.5, and 17.2% for peripheral blood WBCs, lymphocytes, and bone marrow cells, respectively , All three of these values are higher than we have found in other normal h uman cells, compatible with constitutive activation of Ras by cytokines and growth factors present in serum and bone marrow, In 9 of 18 children with T-ALL, Ras activation exceeded two SDs above the mean of the corresponding cells from normal subjects, whereas in none of 11 patients with B-ALL did R as shaw increased activation; activating genetic mutations in ras occur in less than 10% of ALL patients. Thus, Ras is relatively activated in periphe ral blood WBCs, lymphocytes, and bone marrow cells compared with other norm al human cells, and Ras is activated frequently in T-ALL but not in B-ALL, Increased Ras activation in T-ALL compared with B-ALL mag contribute to the more aggressive nature of the former disease.