The role of RAS effectors in BCR/ABL induced chronic myelogenous leukemia

BCR/ABL is the causative agent of chronic myelogenous leukemia(CML).Through structure/function analysis,several protein motifs have been determined to be important for the development of leukemogenesis.Tyrosine177 of BCR is a Grb2 binding site required for BCR/ABL-induced CML in mice.In the current study,we use a mouse bone marrow transduction/transplantation system to demonstrate that addition of oncogenic NRAS(NRASG12D)to a vector containing a BCR/ABL^(Y177F)mutant“rescues”the CML phenotype rapidly and efficiently.To further narrow down the pathways downstream of RAS that are responsible for this rescue effect,we utilize well-characterized RAS effector loop mutants and determine that the RAL pathway is important for rapid induction of CML.Inhibition of this pathway by a dominant negative RAL is capable of delaying disease progression.Results from the present study support the notion of RAL inhibition as a potential therapy for BCR/ABL-induced CML.