BET protein bromodomain inhibitor-based combinations are highly active against post-myeloproliferative neoplasm secondary AML cells.

Abstract

Myeloproliferative neoplasms with myelofibrosis (MPN-MF) demonstrate constitutive activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling that responds to treatment with the JAK1 and 2 kinase inhibitor (JAKi) ruxolitinib. However, MPN-MF often progresses (~20%) to secondary acute myeloid leukemia (sAML), where standard induction chemotherapy or ruxolitinib is relatively ineffective, necessitating the development of novel therapeutic approaches. In the present studies, we demonstrate that treatment with BET (bromodomain and extraterminal) protein inhibitor (BETi), for example, JQ1, inhibits growth and induces apoptosis of cultured and primary, patient-derived (PD), post-MPN sAML blast progenitor cells. Reverse-phase protein array, mass-cytometry and Western analyses revealed that BETi treatment attenuated the protein expressions of c-MYC, p-STAT5, Bcl-xL, CDK4/6, PIM1 and IL-7R, whereas it concomitantly induced the levels of HEXIM1, p21 and BIM in the sAML cells. Co-treatment with BETi and ruxolitinib synergistically induced apoptosis of cultured and PD sAML cells, as well as significantly improved survival of immune-depleted mice engrafted with human sAML cells. Although BETi or heat shock protein 90 inhibitor (HSP90i) alone exerted lethal activity, cotreatment with BETi and HSP90i was synergistically lethal against the ruxolitinib-persister or ruxolitinib-resistant sAML cells. Collectively, these findings further support in vivo testing of BETi-based combinations with JAKi and HSP90i against post-MPN sAML cells.

• Authors: Dyana T Saenz, Warren Fiskus, Taghi Manshouri, Kimal Rajapakshe, Stephanie Krieger, Baohua Sun, Christopher P Mill, Courtney DiNardo, Naveen Pemmaraju, Tapan Kadia, Simrit Parmar, Sunil Sharma, Cristian Coarfa, Peng Qiu, Srdan Verstovsek, Kapil N Bhalla
• Journal: Leukemia (Leukemia) Vol. 31 Issue 3 Pg. 678-687 (03 2017) ISSN: 1476-5551 [Electronic] England
• PMID: 27677740 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biomarkers
• Protein Kinase Inhibitors
• RNA, Messenger
• RNA-Binding Proteins
• Receptors, Interleukin-7
• STAT5 Transcription Factor
• Janus Kinase 2
• Caspases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, genetics)
• Biomarkers
• Caspases (metabolism)
• Cell Line, Tumor
• Disease Models, Animal
• Drug Synergism
• Genes, myc
• High-Throughput Nucleotide Sequencing
• Humans
• Janus Kinase 2 (antagonists & inhibitors, genetics, metabolism)
• Leukemia, Myeloid, Acute (drug therapy, etiology, metabolism, pathology)
• Mice
• Myeloproliferative Disorders (complications)
• Protein Interaction Domains and Motifs (drug effects, genetics)
• Protein Kinase Inhibitors (pharmacology)
• RNA, Messenger (genetics, metabolism)
• RNA-Binding Proteins (antagonists & inhibitors, chemistry, genetics)
• Receptors, Interleukin-7 (metabolism)
• STAT5 Transcription Factor (metabolism)
• Xenograft Model Antitumor Assays