Abstract
Negative feedback regulation of ERK is required for oncogenic transformation in pre-B ALL.
Major finding: Negative feedback regulation of ERK is required for oncogenic transformation in pre-B ALL.
Concept: ERK negative regulators are selectively induced in B-cell lineage leukemia and predict poor outcome.
Impact: Targeted inhibition of DUSP6 induces apoptosis in ALL cells and may overcome TKI resistance.
Pre-B acute lymphoblastic leukemia (ALL) is frequently characterized by RAS pathway mutations and oncogenic tyrosine kinases such as BCR–ABL1 that result in ERK hyperactivation. Treatment with tyrosine kinase inhibitors (TKI) induces remission in patients with Philadelphia chromosome–positive (Ph+) ALL, but tumors frequently relapse due to lesions that drive oncogenic ERK signaling. Shojaee and colleagues demonstrated that, although the majority of pre-B cells died upon acute activation of oncogenes, the small fraction of cells that survived and underwent oncogenic transformation expressed high levels of negative regulators of ERK signaling, including dual specificity phosphatase 6 (DUSP6), ETS variant 5 (ETV5), and Sprouty 2 (SPRY2), which function as tumor suppressors in other tumor types. These negative regulators of ERK were selectively expressed at high levels and associated with poor clinical outcome in human pre-B ALL, but not acute myeloid leukemia. Genetic deletion of Dusp6, Etv5, or Spry2 in pre-B cells prevented oncogenic RAS- and BCR–ABL1-induced malignant transformation in vitro and suppressed the initiation of leukemia in vivo. Loss of ERK negative regulators resulted in hyperactivation of ERK signaling, accumulation of reactive oxygen species, increased p53 protein expression, and the induction of senescence and acute toxicity, indicating that pre-B ALL cells are dependent on robust negative feedback regulation to calibrate ERK signaling. Consistent with these findings, pharmacologic inhibition of DUSP6 in patient-derived Ph+ ALL cells using a small molecule, BCI, resulted in ERK hyperactivation, global loss of tyrosine phosphorylation, and p53-driven cell death. Furthermore, BCI synergized with imatinib and overcame imatinib resistance to induce toxicity in relapsed pre-B ALL cells and patient-derived Ph+ ALL xenografts. These results support the hypothesis that pre-B cells are only permissive to oncogenic signaling in the presence of strong negative feedback control, and suggest that targeting negative regulators of ERK may be effective in pre-B cell ALL.
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