<scp>mTOR</scp> Inhibition improves anaemia and reduces organ damage in a murine model of sickle cell disease

Wang, Jintao; Tran, Jennifer; Wang, Hui; Guo, Chiao; Harro, David; Campbell, Andrew; Eitzman, Daniel T.

doi:10.1111/bjh.14057

Cited by 40 publications

(46 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We next tested whether Rapamycin, a known mTOR inhibitor, may modulate Fyn −/− mouse erythropoiesis as reported for other models of pathologic erythropoiesis. 37,38,42,47 In Fyn −/− mice, Rapamycin administration reduced total erythroblasts, while no significant effects were observed in control animals as previously reported 37,38,42,47 (Figure 4A). (Figure 4B, C).…”

Section: The Mtor Inhibitor Rapamycin Unblocks Autophagy Defect Andsupporting

confidence: 83%

Fyn kinase is a novel modulator of erythropoietin signaling and stress erythropoiesis

et al. 2018

View full text Add to dashboard Cite

The signaling cascade induced by the interaction of erythropoietin (EPO) with its receptor (EPO‐R) is a key event of erythropoiesis. We present here data indicating that Fyn, a Src‐family‐kinase, participates in the EPO signaling‐pathway, since Fyn−/− mice exhibit reduced Tyr‐phosphorylation of EPO‐R and decreased STAT5‐activity. The importance of Fyn in erythropoiesis is also supported by the blunted responsiveness of Fyn−/− mice to stress erythropoiesis. Fyn−/− mouse erythroblasts adapt to reactive oxygen species (ROS) by activating the redox‐related‐transcription‐factor Nrf2. However, since Fyn is a physiologic repressor of Nrf2, absence of Fyn resulted in persistent‐activation of Nrf2 and accumulation of nonfunctional proteins. ROS‐induced over‐activation of Jak2‐Akt‐mTOR‐pathway and repression of autophagy with perturbation of lysosomal‐clearance were also noted. Treatment with Rapamycin, a mTOR‐inhibitor and autophagy activator, ameliorates Fyn−/− mouse baseline erythropoiesis and erythropoietic response to oxidative‐stress. These findings identify a novel multimodal action of Fyn in the regulation of normal and stress erythropoiesis.

show abstract

Section: The Mtor Inhibitor Rapamycin Unblocks Autophagy Defect Andsupporting

confidence: 83%

Fyn kinase is a novel modulator of erythropoietin signaling and stress erythropoiesis

et al. 2018

View full text Add to dashboard Cite

show abstract

“…We next tested whether Rapamycin, a known mTOR inhibitor, may modulate Fyn -/mouse erythropoiesis as reported for other models of pathologic erythropoiesis. 35,36,40,45 In Fyn -/mice, Rapamycin administration reduced total erythroblasts, while no significant effects were observed in control animals as previously reported 35,36,40,45 (Figure 5d). In Fyn -/mice treated with Rapamycin, this was associated with amelioration of the terminal phase of erythropoiesis ( Figure 6Sc).…”

Section: The Mtor Inhibitor Rapamycin Unblocks Autophagy Defect and Asupporting

confidence: 84%

Fyn is Involved in Erythropoietin Signaling Pathway and Interfaces Oxidation to Regulate Erythropoiesis

Beneduce

Falco

Mbiandjeu

et al. 2018

Preprint

View full text Add to dashboard Cite

Erythropoiesis is a complex multistep process responsible of the production of circulating mature erythrocytes and involved the production of reactive oxygen species (ROS) during erythroid differentiation. Here, we document that Fyn, a Srcfamily-kinase, participates in erythropoietin (EPO) signaling pathway, by the reducing extent of Tyr-phosphorylation of EPO-R and by decreasing STAT5 activity. The importance of Fyn in EPO cascade is also supported by the increased sensitivity of Fyn -/mice to stress erythropoiesis. Fyn -/mouse erythroblasts adapt to the induced stress by the activation of the redox-related-transcription-factor Nrf2. However, the absence of the Nrf2 physiologic repressor Fyn resulted in the persistent activation of Nrf2 and accumulation of non-functional proteins. This is paralleled by ROS induced over-activation of Jak2-Akt-mTOR pathway and repression of autophagy and perturbation of lysosomal-clearance during Fyn -/reticulocyte maturation. Treatment with Rapamycin, a mTOR inhibitor and autophagy activator, ameliorates Fyn -/-

show abstract

“…The inhibition of mTOR by Sirolimus has been shown to promote autophagy of mitochondria in human cell hybrid lines carrying pathological mitochondrial DNA mutations. (29) mTOR inhibition has also recently been shown to improve anemia and reduce organ damage in a murine model of SCD(14). In baboons ( P. anubis ), ChIP analysis showed that RN-1 increased the levels of activating chromatin marks (H3K4Me2, H3K4Me3 and H3K9ac) associated with the γ-globin, but not the ε-globin which suggests a specific effect of the drug on γ-globin expression.…”

Section: Discussionmentioning

confidence: 99%

“…Second, we show that RBCs with mitochondria are associated with high levels of ROS accumulation. Finally, we demonstrate that two preclinical candidate drugs, the LSD1 inhibitor, RN-1(12, 13) and mTOR inhibitor(14), Sirolimus, both reduce levels of mitochondria retaining RBCs in a SCD mouse model.…”

Section: Introductionmentioning

confidence: 85%

Pharmacological inhibition of LSD1 and mTOR reduces mitochondrial retention and associated ROS levels in the red blood cells of sickle cell disease

Jagadeeswaran

Vazquez

Thiruppathi

et al. 2017

Experimental Hematology

View full text Add to dashboard Cite

Sickle cell disease (SCD), an inherited blood disorder caused by a point mutation that renders hemoglobin susceptible to polymerization when deoxygenated, affects millions of people worldwide. Manifestations of SCD include chronic hemolytic anemia, inflammation, painful vaso-occlusive crises, multisystem organ damage, and reduced life expectancy. Part of SCD pathophysiology is the excessive formation of intracellular reactive oxygen species (ROS) in SCD red blood cells (RBCs) which accelerates their hemolysis. Normal RBC precursors eliminate their mitochondria during the terminal differentiation process. Strikingly, we observed an increased percentage of RBCs which retain mitochondria in SCD patients’ blood samples compared to healthy individuals In addition, we demonstrate that excessive levels of ROS in SCD are associated with this abnormal mitochondrial retention by an experimental SCD mouse model. Interestingly, LSD1 inhibitor RN-1 and mitophagy inducing agent mTOR inhibitor, Sirolimus, increased red blood cell lifespan and reduced ROS accumulation in parallel with reduction of mitochondria retaining RBCs in the SCD mouse model. Furthermore, gene expression analysis of SCD mice treated with RN-1 showed increased expression of mitophagy genes. Our findings suggest that reduction of mitochondria retaining RBCs may provide a new therapeutic approach to prevent excessive ROS in SCD.

show abstract

mTOR Inhibition improves anaemia and reduces organ damage in a murine model of sickle cell disease

Cited by 40 publications

References 36 publications

Fyn kinase is a novel modulator of erythropoietin signaling and stress erythropoiesis

Fyn kinase is a novel modulator of erythropoietin signaling and stress erythropoiesis

Fyn is Involved in Erythropoietin Signaling Pathway and Interfaces Oxidation to Regulate Erythropoiesis

Pharmacological inhibition of LSD1 and mTOR reduces mitochondrial retention and associated ROS levels in the red blood cells of sickle cell disease

Contact Info

Product

Resources

About