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EFFECTIVENESS OF LSD1 INHIBITION FOR THE TREATMENT OF MPN
Author(s): ,
Jonas Samuel Jutzi
Affiliations:
Clinic for Tumorbiology,University Medical Center,Freiburg,Germany
,
Hugh Rienhoff
Affiliations:
Imago Biosciences,San Francisco,United States
Heike L. Pahl
Affiliations:
Clinic for Tumorbiology,University Medical Center,Freiburg,Germany
(Abstract release date: 05/18/17) EHA Library. Jutzi J. 06/24/17; 181705; S418
Jonas Jutzi
Jonas Jutzi
Contributions
Abstract

Abstract: S418

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 11:45 - 12:00

Location: Hall C

Background

Treatment of MPN with JAK1/2 inhibitors ameliorates symptoms and splenomegaly but does not meaningfully reduce the JAK2V617F allele burden. Though curative, stem cell transplantation is associated with extensive morbidity and mortality highlighting the need for novel effective therapies.
The histone “lysine-specific demethylase 1A” (LSD1/KDM1A) is being explored as a drug target in AML with several inhibitors already in the clinic.  The enzyme is critical for sustaining self-renewal in leukemic initiating cells; inhibiting LSD1 induces monocytic differentiation and reduces engraftment of AML cell in vivo. LSD1 is over-expressed in a number of myeloid diseases including MPN. Preliminary data in a mutant Mpl mouse model of MPN showed that a 28-day course of LSD1 inhibition had a beneficial impact on spleen size, cytokines and mutant cell burden. In a mutant JAK2 mouse model of MPN, we have characterized the disease-modifying activity of the LSD1 inhibitor (IMG-7289), a compound in clinical development for myeloid diseases (NCT02842827).   

Aims

We assessed the pharmacodynamic effects of continuous daily treatment with IMG-7289 in a JAK2V617F knock-in murine MPN with established disease. Animals were treated for up to 56 days. Outcome measures included complete blood counts (CBC), hematological phenotype, overall survival, spleen size, bone marrow morphology and the JAK2V617F allele burden. Moreover, pro-inflammatory cytokine were monitored during the course of treatment as well as chromatin changes by western blotting and ChIPseq.

Methods

Jak2V617F-L2 mice were crossed to MxCRE mice and displayed a fulminant MPN phenotype without dIdC induction. CBC and BM FACS analysis were conducted as previously described. We designed a qPCR assay to quantitate murine JAK2V617F allele burden. 

Results

IMG-7289 treatment was exceptionally well tolerated and mice showed drastic decreases in platelet count (208 vs. 2063*103/μl), reticulocytes (800 vs. 1674*103/μl), monocytes and neutrophils 14 days after the start of treatment. HCT and WBC started to decrease after 28 days. While the JAK2 mutant allele burden increased over time in untreated mice, it decreased in IMG-7289 treated mice and was statistically significantly lower in peripheral blood as well as in spleen. We observed a drastic increase in the pro-inflammatory cytokine CXCL5 in untreated mice during the course of investigation while CXCL5 levels of treated mice decreased to levels of wild-type littermates. Moreover, treated mice showed a highly significantly increased survival over untreated mice, even in a late stage of disease. Lastly, we were able to show that global H3K9me2, which is generally associated with gene expression silencing, was increased in the bone marrow of IMG-7289 treated mice compared to control mice. The remaining pathophysiological data and functional data on epigenetic regulation will be presented. 

Conclusion
The LSD1 inhibitor IMG-7289 normalizes or stabilizes elevated CBCs in a JAK2V617F MPN mouse model. It decreases JAK2 mutant allele burden, pro-inflammatory cytokine levels and confers a clear survival advantage. Our preliminary data show that LSD1 is a potent target with disease-modifying potential in MPN. Clinical studies with IMG-7289 testing this hypothesis have just begun. Owing to its mode of action, altering epigenetics, and the potential reversibility of drug-induced epigenetic remodeling, a long treatment period in MPN patients may be necessary to eliminate disease. Combining IMG-7289 with JAK1/2 inhibitors might accelerate treatment effects. 

Session topic: 15. Myeloproliferative neoplasms - Biology

Keyword(s): Myeloproliferative disorder, Epigenetic

Abstract: S418

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 11:45 - 12:00

Location: Hall C

Background

Treatment of MPN with JAK1/2 inhibitors ameliorates symptoms and splenomegaly but does not meaningfully reduce the JAK2V617F allele burden. Though curative, stem cell transplantation is associated with extensive morbidity and mortality highlighting the need for novel effective therapies.
The histone “lysine-specific demethylase 1A” (LSD1/KDM1A) is being explored as a drug target in AML with several inhibitors already in the clinic.  The enzyme is critical for sustaining self-renewal in leukemic initiating cells; inhibiting LSD1 induces monocytic differentiation and reduces engraftment of AML cell in vivo. LSD1 is over-expressed in a number of myeloid diseases including MPN. Preliminary data in a mutant Mpl mouse model of MPN showed that a 28-day course of LSD1 inhibition had a beneficial impact on spleen size, cytokines and mutant cell burden. In a mutant JAK2 mouse model of MPN, we have characterized the disease-modifying activity of the LSD1 inhibitor (IMG-7289), a compound in clinical development for myeloid diseases (NCT02842827).   

Aims

We assessed the pharmacodynamic effects of continuous daily treatment with IMG-7289 in a JAK2V617F knock-in murine MPN with established disease. Animals were treated for up to 56 days. Outcome measures included complete blood counts (CBC), hematological phenotype, overall survival, spleen size, bone marrow morphology and the JAK2V617F allele burden. Moreover, pro-inflammatory cytokine were monitored during the course of treatment as well as chromatin changes by western blotting and ChIPseq.

Methods

Jak2V617F-L2 mice were crossed to MxCRE mice and displayed a fulminant MPN phenotype without dIdC induction. CBC and BM FACS analysis were conducted as previously described. We designed a qPCR assay to quantitate murine JAK2V617F allele burden. 

Results

IMG-7289 treatment was exceptionally well tolerated and mice showed drastic decreases in platelet count (208 vs. 2063*103/μl), reticulocytes (800 vs. 1674*103/μl), monocytes and neutrophils 14 days after the start of treatment. HCT and WBC started to decrease after 28 days. While the JAK2 mutant allele burden increased over time in untreated mice, it decreased in IMG-7289 treated mice and was statistically significantly lower in peripheral blood as well as in spleen. We observed a drastic increase in the pro-inflammatory cytokine CXCL5 in untreated mice during the course of investigation while CXCL5 levels of treated mice decreased to levels of wild-type littermates. Moreover, treated mice showed a highly significantly increased survival over untreated mice, even in a late stage of disease. Lastly, we were able to show that global H3K9me2, which is generally associated with gene expression silencing, was increased in the bone marrow of IMG-7289 treated mice compared to control mice. The remaining pathophysiological data and functional data on epigenetic regulation will be presented. 

Conclusion
The LSD1 inhibitor IMG-7289 normalizes or stabilizes elevated CBCs in a JAK2V617F MPN mouse model. It decreases JAK2 mutant allele burden, pro-inflammatory cytokine levels and confers a clear survival advantage. Our preliminary data show that LSD1 is a potent target with disease-modifying potential in MPN. Clinical studies with IMG-7289 testing this hypothesis have just begun. Owing to its mode of action, altering epigenetics, and the potential reversibility of drug-induced epigenetic remodeling, a long treatment period in MPN patients may be necessary to eliminate disease. Combining IMG-7289 with JAK1/2 inhibitors might accelerate treatment effects. 

Session topic: 15. Myeloproliferative neoplasms - Biology

Keyword(s): Myeloproliferative disorder, Epigenetic

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