Effect of Ras inhibition in hematopoiesis and BCR/ABL leukemogenesis.

Ras small GTPases are activated in many hematopoietic growth factor signaling and in hematological malignancies, but their role in hematopoiesis and leukemogenesis is not completely known. Here we examined the effect of Ras inhibition by a dominant negative mutant of Ras, N17 H-Ras, in adult hematopoiesis and in BCR/ABL leukemogenesis using the mouse bone marrow transduction and transplantation approach. We found that N17 H-Ras expression suppressed B- and T-lymphopoiesis and erythropoiesis. Interestingly, N17 H-Ras did not suppress myelopoiesis in the bone marrow, yet it greatly attenuated BCR/ABL-induced chronic myelogenous leukemia (CML)-like myeloproliferative disease. Most BCR/ABL + N17 H-Ras mice eventually developed pro-B lymphoblastic leukemia/lymphoma (B-ALL). These results suggest that Ras activation is essential for the development of lymphoid and erythroid cells but not myeloid cells and that Ras is a critical target of BCR/ABL in the pathogenesis of CML, but not B-ALL.