The LSD1 inhibitor RN-1 induces fetal hemoglobin synthesis and reduces disease pathology in sickle cell mice

Cui, Shuaiying; Lim, Kim Chew; Shi, Lihong; Lee, Mary P.; Jearawiriyapaisarn, Natee; Myers, Greggory; Campbell, Andrew; Harro, David; Iwase, Shigeki; Trievel, Raymond C.; Rivers, Angela; DeSimone, Joseph; Lavelle, Donald; Saunthararajah, Yogen; Engel, James Douglas

doi:10.1182/blood-2015-02-626259

Cited by 79 publications

(78 citation statements)

References 53 publications

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“…The results confirm and extend our previous studies in the sickle cell mouse model showing that RN-1 increased F cells, F reticulocytes, and γ-globin mRNA to levels similar to decitabine, the most potent HbF-inducer known. 32,33 However, both these drugs elicit only small increases of γ-globin expression in the SCD mouse model compared to the magnitude observed in baboons, emphasizing the importance of using nonhuman primate, such as baboons, to test the effect of HbFinducing drugs.…”

Section: Discussionmentioning

confidence: 99%

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The LSD1 inhibitor RN-1 recapitulates the fetal pattern of hemoglobin synthesis in baboons (P. anubis)

et al. 2016

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Section: Discussionmentioning

confidence: 99%

“…31 Two recent studies have shown that RN-1, a more potent and specific LSD-1 inhibitor than TCP, induced γ-globin expression in human and baboon erythroid progenitors and a sickle cell mouse model. 32,33 In this study we have tested the effect of RN-1 in baboons and confirm that it is a highly potent in vivo inducer of HbF synthesis.…”

mentioning

confidence: 99%

The LSD1 inhibitor RN-1 recapitulates the fetal pattern of hemoglobin synthesis in baboons (P. anubis)

et al. 2016

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“…In addition, the contribution of LSD1 in leukemogenesis has been demonstrated, and the use of LSD1 inhibitors is being investigated as a new therapeutic strategy (49,50). The roles of LSD1 in hematopoiesis are various, and include the differentiation switch between erythropoiesis and myelopoiesis (44), the terminal differentiation of some hematopoietic lineages (47,48), maintenance of the undifferentiated state of plasma cells (46), globin switching (51)(52)(53), and the self-renewal of hematopoietic stem cells (48). Here, we unveiled new roles of LSD1, as a down-regulator of the endothelial characteristics and promoter of the hematopoietic commitment in hemangioblasts.…”

Section: Discussionmentioning

confidence: 99%

LSD1/KDM1A promotes hematopoietic commitment of hemangioblasts through downregulation of Etv2

Takeuchi

Fuse

Watanabe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The hemangioblast is a progenitor cell with the capacity to give rise to both hematopoietic and endothelial progenitors. Currently, the regulatory mechanisms underlying hemangioblast formation are being elucidated, whereas those controllers for the selection of hematopoietic or endothelial fates still remain a mystery. To answer these questions, we screened for zebrafish mutants that have defects in the hemangioblast expression of Gata1, which is never expressed in endothelial progenitors. One of the isolated mutants, it627, showed not only down-regulation of hematopoietic genes but also up-regulation of endothelial genes. We identified the gene responsible for the it627 mutant as the zebrafish homolog of Lys-specific demethylase 1 (LSD1/KDM1A). Surprisingly, the hematopoietic defects in lsd1it627 embryos were rescued by the gene knockdown of the Ets variant 2 gene (etv2), an essential regulator for vasculogenesis. Our results suggest that the LSD1-dependent shutdown of Etv2 gene expression may be a significant event required for hemangioblasts to initiate hematopoietic differentiation.

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“…35 Subsequent studies showed inhibition of erythroid maturation by tranylcypromine, which precludes further clinical development. However, another LDS1 inhibitor, RN-1, was recently shown to induce HbF in sickle cell mice with increased F-cells 36 and decreased numbers of sickle red cells in the peripheral blood, suggesting RN-1 may also reduce disease pathology.…”

Section: Modulation Of Epigenetic Marks To Activate Hbf Expressionmentioning

confidence: 99%

Cell signaling pathways involved in drug-mediated fetal hemoglobin induction: Strategies to treat sickle cell disease

Pace

Liu

et al. 2015

Exp Biol Med (Maywood)

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The developmental regulation of globin gene expression has shaped research efforts to establish therapeutic modalities for individuals affected with sickle cell disease and b-thalassemia. Fetal hemoglobin has been shown to block sickle hemoglobin S polymerization to improve symptoms of sickle cell disease; moreover, fetal hemoglobin functions to replace inadequate hemoglobin A synthesis in b-thalassemia thus serving as an effective therapeutic target. In the perinatal period, fetal hemoglobin is synthesized at high levels followed by a decline to adult levels by one year of age. It is known that naturally occurring mutations in the g-globin gene promoters and distant cis-acting transcription factors produce persistent fetal hemoglobin synthesis after birth to ameliorate clinical symptoms. Major repressor proteins that silence g-globin during development have been targeted for gene therapy in b-hemoglobinopathies patients. In parallel effort, several classes of pharmacological agents that induce fetal hemoglobin expression through molecular and cell signaling mechanisms have been identified. Herein, we reviewed the progress made in the discovery of signaling molecules targeted by pharmacologic agents that enhance g-globin expression and have the potential for future drug development to treat the b-hemoglobinopathies.

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The LSD1 inhibitor RN-1 induces fetal hemoglobin synthesis and reduces disease pathology in sickle cell mice

Abstract: Key Points RN-1 treatment of SCD mice results in increased human fetal γ-globin induction and fetal hemoglobin synthesis. RN-1 treatment of SCD mice significantly reduces sickling, hemolysis, and tissue injury with no obvious adverse side effects.

Cited by 79 publications

References 53 publications

The LSD1 inhibitor RN-1 recapitulates the fetal pattern of hemoglobin synthesis in baboons (P. anubis)

The LSD1 inhibitor RN-1 recapitulates the fetal pattern of hemoglobin synthesis in baboons (P. anubis)

LSD1/KDM1A promotes hematopoietic commitment of hemangioblasts through downregulation of Etv2

Cell signaling pathways involved in drug-mediated fetal hemoglobin induction: Strategies to treat sickle cell disease

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