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HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans

Sachie Marubayashi1, Priya Koppikar, Tony Taldone

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

The Journal of Clinical Investigation
|September 21, 2010
PubMed

Insights

HSP90 inhibitor PU-H71 effectively treats myeloproliferative neoplasms (MPNs) by degrading JAK2 protein, showing promise for polycythemia vera and essential thrombocytosis models with reduced toxicity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Activating JAK2 mutations drive myeloproliferative neoplasms (MPNs).
  • Current JAK2 inhibitors show limited efficacy and toxicity in MPN treatment.
  • Novel therapeutic strategies targeting JAK2 are needed for MPNs.

Purpose of the Study:

  • To investigate the efficacy of HSP90 inhibitor PU-H71 in JAK2-dependent MPNs.
  • To determine if PU-H71 disrupts JAK2 protein stability and impacts MPN progression.
  • To establish a therapeutic rationale for HSP90 inhibition in MPN treatment.

Main Methods:

  • Assessed PU-H71 efficacy in MPN cell lines and mouse models.
  • Investigated JAK2 protein association with HSP90 and degradation by PU-H71.
  • Evaluated JAK-STAT signaling, cell growth, and peripheral blood counts in treated mice.
  • Determined the effect of PU-H71 on mutant allele burden in vivo.

Main Results:

  • PU-H71 treatment degraded JAK2 protein in vitro and in vivo.
  • PU-H71 inhibited cell growth and JAK-STAT signaling in JAK2-mutant cells and MPN samples.
  • Mice treated with PU-H71 showed normalized blood counts, improved survival, and reduced mutant allele burden.
  • PU-H71 demonstrated efficacy at non-toxic doses in normal tissues.

Conclusions:

  • JAK2 is an HSP90 chaperone client protein.
  • HSP90 inhibition by PU-H71 represents a novel therapeutic strategy for JAK2-dependent MPNs.
  • PU-H71 shows significant therapeutic potential for polycythemia vera and essential thrombocytosis.

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