Acute lymphoblastic leukemia (ALL) represents the most frequent type of cancer in children and occurs in adults as well. The BCR-ABL1 oncogene promotes leukemia through initiation of a strong signaling cascade including activation of the Ras-MAPK pathway. In preliminary studies for this proposal, we have made the unexpected observation that three inhibitory molecules that attenuate Ras-MAPK signaling, DUSP6, SPRY2 and ETV5, are actually required for the survival of leukemia cells. This was against our expectations, because we hypothesized that stronger signaling of the BCR-ABL1 oncogene through Ras-MAPK would result in a more aggressive leukemia. In fact, however, leukemia cells died when the strength of the Ras-MAPK pathway was increased. The main goals of this proposal are

(1) to understand why negative feedback regulation is required for the survival of leukemia cells,

(2) to understand the precise mechanism of negative feedback regulation and

(3) to leverage this information towards the development of a new therapy concept based on pharmacological hyperactivation of Ras-MAPK signaling.