Defective K-Ras oncoproteins overcome impaired effector activation to initiate leukemia in vivo.

ABSTRACT: Reversing the aberrant biochemical output of oncogenic Ras proteins is one of the great challenges in cancer therapeutics; however, it is uncertain which Ras effectors are required for tumor initiation and maintenance. To address this question, we expressed oncogenic K-Ras(D12) proteins with "second site" amino acid substitutions that impair PI3 kinase/Akt or Raf/MEK/ERK activation in bone marrow cells and transplanted them into recipient mice. In spite of attenuated signaling properties, defective K-Ras oncoproteins initiated aggressive clonal T-lineage acute lymphoblastic leukemia (T-ALL). Murine T-ALLs expressing second site mutant proteins restored full oncogenic Ras activity through diverse mechanisms, which included acquiring novel somatic third site Kras(D12) mutations and silencing

SUBMITTER: Shieh A 

PROVIDER: S-EPMC3682340 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature