LSD1 Inhibition Prolongs Survival in Mouse Models of MPN by Selectively Targeting the Disease Clone
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 o...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2018-06-01
|
| Series: | HemaSphere |
| Online Access: | http://journals.lww.com/10.1097/HS9.0000000000000054 |
| _version_ | 1797285136940662784 |
|---|---|
| author | Jonas S. Jutzi Maria Kleppe Jennifer Dias Hans Felix Staehle Kaitlyn Shank Julie Teruya-Feldstein Sudheer Madan Mohan Gambheer Christine Dierks Hugh Y. Rienhoff, Jr Ross L. Levine Heike L. Pahl |
| author_facet | Jonas S. Jutzi Maria Kleppe Jennifer Dias Hans Felix Staehle Kaitlyn Shank Julie Teruya-Feldstein Sudheer Madan Mohan Gambheer Christine Dierks Hugh Y. Rienhoff, Jr Ross L. Levine Heike L. Pahl |
| author_sort | Jonas S. Jutzi |
| collection | DOAJ |
| description | 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 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. |
| first_indexed | 2024-03-07T17:57:55Z |
| format | Article |
| id | doaj.art-9a5226cfef28450b8b2347a82de72292 |
| institution | Directory Open Access Journal |
| issn | 2572-9241 |
| language | English |
| last_indexed | 2024-03-07T17:57:55Z |
| publishDate | 2018-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | HemaSphere |
| spelling | doaj.art-9a5226cfef28450b8b2347a82de722922024-03-02T11:34:38ZengWileyHemaSphere2572-92412018-06-012310.1097/HS9.0000000000000054201806000-00011LSD1 Inhibition Prolongs Survival in Mouse Models of MPN by Selectively Targeting the Disease CloneJonas S. JutziMaria KleppeJennifer DiasHans Felix StaehleKaitlyn ShankJulie Teruya-FeldsteinSudheer Madan Mohan GambheerChristine DierksHugh Y. Rienhoff, JrRoss L. LevineHeike L. PahlAbstract. 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.http://journals.lww.com/10.1097/HS9.0000000000000054 |
| spellingShingle | Jonas S. Jutzi Maria Kleppe Jennifer Dias Hans Felix Staehle Kaitlyn Shank Julie Teruya-Feldstein Sudheer Madan Mohan Gambheer Christine Dierks Hugh Y. Rienhoff, Jr Ross L. Levine Heike L. Pahl LSD1 Inhibition Prolongs Survival in Mouse Models of MPN by Selectively Targeting the Disease Clone HemaSphere |
| title | LSD1 Inhibition Prolongs Survival in Mouse Models of MPN by Selectively Targeting the Disease Clone |
| title_full | LSD1 Inhibition Prolongs Survival in Mouse Models of MPN by Selectively Targeting the Disease Clone |
| title_fullStr | LSD1 Inhibition Prolongs Survival in Mouse Models of MPN by Selectively Targeting the Disease Clone |
| title_full_unstemmed | LSD1 Inhibition Prolongs Survival in Mouse Models of MPN by Selectively Targeting the Disease Clone |
| title_short | LSD1 Inhibition Prolongs Survival in Mouse Models of MPN by Selectively Targeting the Disease Clone |
| title_sort | lsd1 inhibition prolongs survival in mouse models of mpn by selectively targeting the disease clone |
| url | http://journals.lww.com/10.1097/HS9.0000000000000054 |
| work_keys_str_mv | AT jonassjutzi lsd1inhibitionprolongssurvivalinmousemodelsofmpnbyselectivelytargetingthediseaseclone AT mariakleppe lsd1inhibitionprolongssurvivalinmousemodelsofmpnbyselectivelytargetingthediseaseclone AT jenniferdias lsd1inhibitionprolongssurvivalinmousemodelsofmpnbyselectivelytargetingthediseaseclone AT hansfelixstaehle lsd1inhibitionprolongssurvivalinmousemodelsofmpnbyselectivelytargetingthediseaseclone AT kaitlynshank lsd1inhibitionprolongssurvivalinmousemodelsofmpnbyselectivelytargetingthediseaseclone AT julieteruyafeldstein lsd1inhibitionprolongssurvivalinmousemodelsofmpnbyselectivelytargetingthediseaseclone AT sudheermadanmohangambheer lsd1inhibitionprolongssurvivalinmousemodelsofmpnbyselectivelytargetingthediseaseclone AT christinedierks lsd1inhibitionprolongssurvivalinmousemodelsofmpnbyselectivelytargetingthediseaseclone AT hughyrienhoffjr lsd1inhibitionprolongssurvivalinmousemodelsofmpnbyselectivelytargetingthediseaseclone AT rossllevine lsd1inhibitionprolongssurvivalinmousemodelsofmpnbyselectivelytargetingthediseaseclone AT heikelpahl lsd1inhibitionprolongssurvivalinmousemodelsofmpnbyselectivelytargetingthediseaseclone |