Enasidenib drives human erythroid differentiation independently of isocitrate dehydrogenase 2

Dutta, Ritika; Zhang, Tian Yi; Köhnke, Thomas; Thomas, Daniel; Linde, Miles H.; Gars, Eric J.; Stafford, Melissa; Kaur, Satinder; Nakauchi, Yusuke; Yin, Raymond; Azizi, Armon; Narla, Anupama; Majeti, Ravindra

doi:10.1172/jci133344

Cited by 26 publications

(17 citation statements)

References 31 publications

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“…Interestingly, enasidenib was found to act independently of IDH2 on EPCs. Enasidenib potently promotes erythroid differentiation through the modulation of protoporphyrin IX (PPIX) accumulation and hemoglobin production in late-stage EPCs [ 288 ]. As a result, increased hemoglobin concentration and RBC transfusion independence were reported for enasidenib-treated patients [ 287 , 289 ].…”

Section: Modulation Of Epcs To Inhibit Their Tumor-promoting Effecmentioning

confidence: 99%

Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

Grzywa

Justyniarska

Nowis

et al. 2021

Cancers

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Cancer cells harness normal cells to facilitate tumor growth and metastasis. Within this complex network of interactions, the establishment and maintenance of immune evasion mechanisms are crucial for cancer progression. The escape from the immune surveillance results from multiple independent mechanisms. Recent studies revealed that besides well-described myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) or regulatory T-cells (Tregs), erythroid progenitor cells (EPCs) play an important role in the regulation of immune response and tumor progression. EPCs are immature erythroid cells that differentiate into oxygen-transporting red blood cells. They expand in the extramedullary sites, including the spleen, as well as infiltrate tumors. EPCs in cancer produce reactive oxygen species (ROS), transforming growth factor β (TGF-β), interleukin-10 (IL-10) and express programmed death-ligand 1 (PD-L1) and potently suppress T-cells. Thus, EPCs regulate antitumor, antiviral, and antimicrobial immunity, leading to immune suppression. Moreover, EPCs promote tumor growth by the secretion of growth factors, including artemin. The expansion of EPCs in cancer is an effect of the dysregulation of erythropoiesis, leading to the differentiation arrest and enrichment of early-stage EPCs. Therefore, anemia treatment, targeting ineffective erythropoiesis, and the promotion of EPC differentiation are promising strategies to reduce cancer-induced immunosuppression and the tumor-promoting effects of EPCs.

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Section: Modulation Of Epcs To Inhibit Their Tumor-promoting Effecmentioning

confidence: 99%

Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

Grzywa

Justyniarska

Nowis

et al. 2021

Cancers

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show abstract

“…Yet another protein shown to be involved in heme export is ABCG2, also known as the breast cancer resistance protein (BRCP). ABCG2 is an ATP-binding cassette transporter which has been shown to transport heme, hemin and porphyrin in addition to a variety of medications [217][218][219][220][221]. ABCG2 is expressed by a variety of normal tissues including placenta, brain, small intestines, ovary, liver and hematopoetic stem cells, as well as in a number of cancer cells [222].…”

Section: Exogenous Vs Endogenous Hemementioning

confidence: 99%

From Synthesis to Utilization: The Ins and Outs of Mitochondrial Heme

Swenson

Moore

Marcero

et al. 2020

Cells

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Heme is a ubiquitous and essential iron containing metallo-organic cofactor required for virtually all aerobic life. Heme synthesis is initiated and completed in mitochondria, followed by certain covalent modifications and/or its delivery to apo-hemoproteins residing throughout the cell. While the biochemical aspects of heme biosynthetic reactions are well understood, the trafficking of newly synthesized heme—a highly reactive and inherently toxic compound—and its subsequent delivery to target proteins remain far from clear. In this review, we summarize current knowledge about heme biosynthesis and trafficking within and outside of the mitochondria.

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“…Moreover, secretion of hEPO protein as a hormone into blood were also confirmed in AdEPO mice. The gene expression of Gata1 (regulator of hematopoietic signaling) [31,32], Gypa, and Trfr (specific markers of RBCs) [33][34][35], were drastically increased in the spleens of AdEPO mice. Furthermore, the RBC count, Hgb level, and HCT were increased in AdEPO mice.…”

Section: Discussionmentioning

confidence: 99%

Proof of Gene Doping in a Mouse Model with a Human Erythropoietin Gene Transferred Using an Adenoviral Vector

Sugasawa¹,

Nakano²,

Fujita³

et al. 2021

Preprint

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The World Anti-Doping Agency (WADA) has prohibited gene doping in the context of progress in gene therapy. In addition, there is a risk of the EPO gene being applied in gene doping among athletes. Along with this, development of a gene-doping test has been underway in worldwide. Here, we had two purposes: to develop a robust gene doping mouse model using the human EPO gene (hEPO) transferred using recombinant adenovirus (rAdV) as a vector and to develop a detection method to prove gene doping using this model. The rAdV including the hEPO gene were injected intravenously to transfer the gene to the liver. After injection, the mice developed significantly increased red blood cell counts in whole blood and increased gene expressions of hematopoietic markers in the spleen, indicating successful development of the gene doping model. Next, we detected direct and indirect proof of gene doping in whole blood DNA and RNA using qPCR assay and RNA sequencing. Proof was detected in one drop of whole blood DNA and RNA over a long period; furthermore, the overall RNA expression profiles significantly changed. Therefore, we have advanced detection of hEPO gene doping in humans.

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Enasidenib drives human erythroid differentiation independently of isocitrate dehydrogenase 2

Cited by 26 publications

References 31 publications

Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

From Synthesis to Utilization: The Ins and Outs of Mitochondrial Heme

Proof of Gene Doping in a Mouse Model with a Human Erythropoietin Gene Transferred Using an Adenoviral Vector

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