2. Academic Validation
  3. LSD1 Inhibition Prolongs Survival in Mouse Models of MPN by Selectively Targeting the Disease Clone

LSD1 Inhibition Prolongs Survival in Mouse Models of MPN by Selectively Targeting the Disease Clone

  • Hemasphere. 2018 Jun 8;2(3):e54. doi: 10.1097/HS9.0000000000000054.
Jonas S Jutzi 1 2 3,  Maria Kleppe 4 5 6,  Jennifer Dias 7,  Hans Felix Staehle 1,  Kaitlyn Shank 4,  Julie Teruya-Feldstein 8,  Sudheer Madan Mohan Gambheer 1,  Christine Dierks 1,  Hugh Y Rienhoff Jr 7,  Ross L Levine 4 5 6 9,  Heike L Pahl 1 2
Affiliations

Affiliations

  • 1 Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Center for Tumor Biology, Freiburg, Germany.
  • 2 Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany.
  • 3 Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • 4 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 5 Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 6 Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 7 Imago BioSciences, San Francisco, CA, USA.
  • 8 Department of Pathology, Icahn School of Medicine, Mount Sinai, New York, NY, USA.
  • 9 Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
PMID: 31723778 DOI: 10.1097/HS9.0000000000000054
Abstract

Despite recent advances, the myeloproliferative neoplasms (MPNs) are attended by considerable morbidity and mortality. Janus kinase (JAK) inhibitors such as ruxolitinib manage symptoms but do not substantially change the natural history of the disease. In this report, we show the effects of IMG-7289, an irreversible inhibitor of the epigenetically active lysine-specific demethylase 1 (LSD1) in mouse models of MPN. Once-daily treatment with IMG-7289 normalized or improved blood cell counts, reduced spleen volumes, restored normal splenic architecture, and reduced bone marrow fibrosis. Most importantly, LSD1 inhibition lowered mutant allele burden and improved survival. IMG-7289 selectively inhibited proliferation and induced Apoptosis of JAK2 V617F cells by concomitantly increasing expression and methylation of p53, and, independently, the pro-apoptotic factor PUMA and by decreasing the levels of its antiapoptotic antagonist BCLXL. These data provide a molecular understanding of the disease-modifying activity of the LSD1 inhibitor IMG-7289 that is currently undergoing clinical evaluation in patients with high-risk myelofibrosis. Moreover, low doses of IMG-7289 and ruxolitinib synergize in normalizing the MPN phenotype in mice, offering a rationale for investigating combination therapy.

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