title: The role of RAS effectors in BCR/ABL induced chronic myelogenous leukemia.
abstract: 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.
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Jessica
authors.initials: J
authors.lastname: Fredericks
authors.forename: Ruibao
authors.initials: R
authors.lastname: Ren
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D063646:Carcinogenesis / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D012190:Retroviridae; D020725:ral GTP-Binding Proteins / Q000378:metabolism*; D020726:ral Guanine Nucleotide Exchange Factor / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D020726:ral Guanine Nucleotide Exchange Factor; D020725:ral GTP-Binding Proteins; D018631:ras Proteins