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Ref Type Journal Article
PMID (31723778)
Authors Jutzi JS, Kleppe M, Dias J, Staehle HF, Shank K, Teruya-Feldstein J, Gambheer SMM, Dierks C, Rienhoff HY, Levine RL, Pahl HL
Title LSD1 Inhibition Prolongs Survival in Mouse Models of MPN by Selectively Targeting the Disease Clone.
Journal HemaSphere
Vol 2
Issue 3
Date 2018 Jun
URL
Abstract Text 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 JAK2V617F 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK2 V617F TP53 R248W acute myeloid leukemia predicted - sensitive IMG-7289 + Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, combination treatment with Jakafi (ruxolitinib) and IMG-7289 led to synergistic inhibition of colony formation and apoptosis induction in an acute myeloid leukemia cell line harboring JAK2 V617F and TP53 R248W in culture (PMID: 31723778). 31723778
JAK2 V617F hematologic cancer predicted - sensitive IMG-7289 Preclinical - Cell culture Actionable In a preclinical study, IMG-7289 treatment led to increased apoptosis induction in transformed cells expressing JAK2 V617F compared to cells expressing wild-type Jak2 in culture (PMID: 31723778). 31723778
JAK2 V617F TP53 R248W acute myeloid leukemia predicted - sensitive IMG-7289 Preclinical - Cell culture Actionable In a preclinical study, IMG-7289 treatment led to inhibition of colony formation, increased apoptosis and induction of cell cycle arrest in an acute myeloid leukemia cell line harboring JAK2 V617F and TP53 R248W in culture (PMID: 31723778). 31723778
JAK2 V617F myeloproliferative neoplasm sensitive IMG-7289 Preclinical Actionable In a preclinical study, IMG-7289 treatment led to decreased JAK2 V617F allele burden in peripheral blood cells and splenic cells, decreased spleen size, and improved survival in a transgenic mouse model of myeloproliferative neoplasm expressing JAK2 V617F (PMID: 31723778). 31723778
JAK2 V617F myeloproliferative neoplasm predicted - sensitive IMG-7289 + Ruxolitinib Preclinical Actionable In a preclinical study, combination treatment with Jakafi (ruxolitinib) and IMG-7289 demonstrated a synergistic effect, and led to decreased leukocyte and platelet counts, decreased spleen size, and decreased bone marrow stem and progenitor cell expansion in a transgenic mouse model expressing JAK2 V617F (PMID: 31723778). 31723778