Negative feedback enables oncogenic signaling in pre-B cells and represents a therapeutic target in acute lymphoblastic leukemia

ABSTRACT: Targeted therapy of cancer typically focuses on the development of agents that will inactivate a transforming oncogene. In this study, we tested the concept that besides the oncogene itself, factors that enable permissiveness of a normal cell to oncogenic signaling represent a novel class of therapeutic targets. This hypothesis was based on our finding that acute activation of oncogenes in normal pre-B cells typically results in immediate cell death, unless pre-B cells were capable of adapting quickly enough to a high level of signaling output in Erk and Stat5 pathways. Surviving pre-B cell clones achieved permissiveness to oncogenic signaling by strong upregulation of negative feedback regulators of Erk (DUSP6, SPRY2, ETV5) and Stat5 (CISH, SOCS2, SOCS3) signaling. Genetic deletion of the sprouty family Ras inhibitor Spry2, the Erk phosphatase Dusp6 or Etv5, a transcriptional activator of SPRY2/DUSP6, decreased robustness of negative feedback control and compromised oncogenic transformation. Likewise, ablation of the suppressors of cytokine signaling (SOCS) family molecules Cish, Socs2 and Socs3 reversed permissiveness of pre-B cells to oncogenic signaling. Searching for factors that limit permissiveness of normal pre-B cells to oncogene signaling, we identified the lymphoid transcription factor IKZF1, which functions as a critical tumor suppressor in pre-B ALL. IKZF1 binds directly to and transcriptionally represses DUSP6, SPRY2, ETV5, CISH, SOCS2, and SOCS3 promoters, hence lowering the threshold of maximum allowable oncogene signaling strength. Interstingly, a small molecule inhibitor of DUSP6 acutely subverted negative feedback regulation and selectively induced cell death in pre-B ALL cells. In addition, small molecule inhibition of DUSP6 was sufficient to overcome conventional mechanisms of drug-resistance in pre-B ALL and had strong selective activity on drug-resistant patient-derived pre-B ALL cells that were injected into NOD/SCID transplant recipient mice. These findings identify permissive negative feedback control of oncogenic signaling as a previously unrecognized vulnerability of pre-B ALL cells and a new class of potential therapeutic targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE58739 | GEO | 2017/01/12

SECONDARY ACCESSION(S): PRJNA253306

REPOSITORIES: GEO