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MAPK-negative feedback regulation confers dependence to JAK2V617F signaling

Meenu Kesarwani1, Zachary Kincaid1, Mohammad Azhar1

  • 1Division of Pathology, Cincinnati Children's Hospital, Cincinnati, OH, USA.

Leukemia
|July 10, 2023
PubMed

Insights

Targeting DUSP1 may offer a cure for JAK2V617F-driven myeloproliferative neoplasms (MPNs). This approach overcomes treatment resistance by restoring p53 levels and inducing synthetic lethality in cancer cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Hematology

Background:

  • JAK2 kinase inhibitor (TKI) therapy is often ineffective for myeloproliferative neoplasms (MPNs) due to compensatory survival pathways.
  • Reactivation of MEK-ERK and PI3K pathways, sustained by inflammatory cytokines, leads to treatment failure in MPNs.

Purpose of the Study:

  • To investigate the role of cytokine signaling in JAK2V617F-induced MPNs and its impact on treatment resistance.
  • To explore the potential of targeting DUSP1 for a curative response in JAK2V617F-driven MPNs.

Main Methods:

  • Investigated the convergence of JAK2V617F and cytokine signaling on DUSP1 expression.
  • Assessed the effect of DUSP1 deletion and inhibition on p53 stabilization and apoptosis in JAK2V617F cells.
  • Evaluated the clonal selectivity of DUSP1 inhibition using small molecule inhibitors and ectopic DUSP6 expression.

Main Results:

  • JAK2V617F and cytokine signaling converge to enhance DUSP1 expression, which inhibits p53 stabilization and increases the apoptotic threshold.
  • DUSP1 deletion leads to synthetic lethality in JAK2V617F-expressing cells by increasing p53 levels.
  • Selective DUSP1 inhibition combined with DUSP6 restoration eradicates JAK2V617F cells, overcoming resistance.

Conclusions:

  • Inflammatory cytokines and JAK2V617F signaling induce DUSP1, downregulating p53 and causing TKI resistance in MPNs.
  • Targeting DUSP1, particularly in combination with strategies to manage compensatory pathways like DUSP6, shows promise for curative treatment in JAK2V617F-driven MPNs.

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