Effect of congenital upregulation of hypoxia inducible factors on percentage of fetal hemoglobin in the blood

Salomon-Andonie, Juan; Miasnikova, Galina Y.; Sergueeva, Adelina; Polyakova, Lydia A.; Niu, Xiaomei; Nekhai, Sergeï

doi:10.1182/blood-2013-07-515973

Cited by 7 publications

(6 citation statements)

References 10 publications

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“…As there are reports of increased HbF in individuals exposed to hypoxia 16 , we also quantitated HbF in 29 additional Tibetan subjects living at 4320 m, 25 Aymara and 5 Caucasian Andean residents and all of them had normal HbF. Our data are consistent with a recent report of normal HbF in subjects with Chuvash polycythemia who have aberrant hypoxia sensing due to an underlying von Hippel-Lindau gene mutation that leads to augmented hypoxia sensing at low altitudes 17 .…”

Section: Resultssupporting

confidence: 87%

High altitude genetic adaptation in Tibetans: No role of increased hemoglobin–oxygen affinity

Tashi

Tian

Koul

et al. 2014

Blood Cells, Molecules, and Diseases

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High altitude exerts selective evolutionary pressure primarily due to its hypoxic environment, resulting in multiple adaptive responses. High hemoglobin-oxygen affinity is postulated to be one such adaptive change, which has been reported in Sherpas of the Himalayas. Tibetans have lived on the Qinghai-Tibetan plateau for thousands of years and have developed unique phenotypes, such as protection from polycythemia which has been linked to PDH2 mutation, resulting in downregulation of HIF pathway. In order to see if Tibetans also developed high hemoglobin-oxygen affinity as a part of their genetic adaptation, we conducted this study assessing hemoglobin-oxygen affinity and their fetal hemoglobin levels in Tibetan subjects from 3 different altitudes. We found normal hemoglobin-oxygen affinity in all subjects, fetal hemoglobin levels were normal in all except one and no hemoglobin variants in any of the subjects. We conclude that increased hemoglobin-oxygen affinity or increased fetal hemoglobin are not adaptive phenotypes of the Tibetan highlanders.

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Section: Resultssupporting

confidence: 87%

High altitude genetic adaptation in Tibetans: No role of increased hemoglobin–oxygen affinity

Tashi

Tian

Koul

et al. 2014

Blood Cells, Molecules, and Diseases

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“…This specific issue was not addressed by the present study. However, hypoxia, a condition stimulating HbF in erythroid cells [51] , is also associated with the decrease of mTORC1 activity [52] and alteration of the control of protein synthesis [53] .…”

Section: Discussionmentioning

confidence: 99%

Erythroid induction of K562 cells treated with mithramycin is associated with inhibition of raptor gene transcription and mammalian target of rapamycin complex 1 (mTORC1) functions

Finotti¹,

Bianchi²,

Fabbri³

et al. 2015

Pharmacological Research

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“… 19 In contrast, patients harboring a homozygous VHL mutation (598C>T) do not exhibit increased HbF, despite increased serum EPO level, a result of HIF pathway activation. 20 Here, we wished to clarify whether VHL plays a role in HbF repression and if the latter role is mediated via the HIF signaling pathway.…”

Section: Resultsmentioning

confidence: 99%

Identification of novel γ-globin inducers among all potential erythroid druggable targets

Myers

Schneider

et al. 2022

Blood Advances

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Human γ-globin is predominantly expressed in fetal liver erythroid cells during gestation from two nearly identical genes, HBG1 and HBG2, that are both perinatally silenced. Reactivation of these fetal genes in adult red blood cells can ameliorate many symptoms associated with the inherited β-globinopathies, sickle cell disease (SCD) and Cooley's anemia. While promising genetic strategies to reactivate the γ-globin genes to treat these diseases have been explored, there are significant barriers to their effective implementation worldwide; alternatively, pharmacological induction of γ-globin synthesis could readily reach the majority of affected individuals. In this study, we generated a CRISPR knockout library that targeted all erythroid genes for which prospective or actual therapeutic compounds already exist. By probing this library for genes that repress fetal hemoglobin (HbF), we identified several novel, potentially druggable, γ-globin repressors, including VHL and PTEN. We demonstrate that deletion of VHL induces HbF through activation of the HIF1α pathway and that deletion of PTEN induces HbF through AKT pathway stimulation. Finally, we show that small molecule inhibitors of PTEN and EZH induce HbF in both healthy and β-thalassemic human primary erythroid cells.

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Effect of congenital upregulation of hypoxia inducible factors on percentage of fetal hemoglobin in the blood

Cited by 7 publications

References 10 publications

High altitude genetic adaptation in Tibetans: No role of increased hemoglobin–oxygen affinity

High altitude genetic adaptation in Tibetans: No role of increased hemoglobin–oxygen affinity

Erythroid induction of K562 cells treated with mithramycin is associated with inhibition of raptor gene transcription and mammalian target of rapamycin complex 1 (mTORC1) functions

Identification of novel γ-globin inducers among all potential erythroid druggable targets

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