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BET protein bromodomain inhibitor-based combinations are highly active against post-myeloproliferative neoplasm

Dyana T Saenz1, Warren Fiskus1, Taghi Manshouri1

  • 1Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston TX, 77030.

Leukemia
|September 29, 2016
PubMed

Insights

BET protein inhibitors (BETi) show promise against secondary acute myeloid leukemia (sAML) that arises from myeloproliferative neoplasms (MPN). Combining BETi with JAK inhibitors (JAKi) or HSP90 inhibitors (HSP90i) offers synergistic therapeutic potential for difficult-to-treat sAML.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Myeloproliferative neoplasms with myelofibrosis (MPN-MF) involve Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation, treatable with JAK inhibitors (JAKi) like ruxolitinib.
  • Progression of MPN-MF to secondary acute myeloid leukemia (sAML) occurs in ~20% of cases, with limited therapeutic options including standard chemotherapy and JAKi.

Purpose of the Study:

  • To investigate the efficacy of BET (bromodomain and extraterminal) protein inhibitors (BETi) against post-MPN sAML.
  • To evaluate combination therapies involving BETi with JAKi and heat shock protein 90 inhibitors (HSP90i) for sAML treatment.

Main Methods:

  • Treatment of cultured and patient-derived (PD) sAML cells with BETi (e.g., JQ1).
  • Analysis of protein expression changes using reverse-phase protein array, mass-cytometry, and Western blot.
  • In vivo studies using immune-depleted mice engrafted with human sAML cells, evaluating co-treatments with BETi, JAKi, and HSP90i.

Main Results:

  • BETi treatment inhibited sAML cell growth and induced apoptosis by modulating key proteins including c-MYC, p-STAT5, Bcl-xL, and p21.
  • Co-treatment with BETi and ruxolitinib synergistically enhanced apoptosis and improved survival in a mouse model of sAML.
  • Combined BETi and HSP90i demonstrated synergistic lethality against ruxolitinib-resistant sAML cells.

Conclusions:

  • BET inhibitors represent a promising therapeutic strategy for post-MPN sAML.
  • Combination therapies of BETi with JAKi or HSP90i show significant potential for overcoming treatment resistance in sAML.

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