Targeting elevated heme levels to treat a mouse model for Diamond-Blackfan Anemia

Sjögren, S.; Mattebo, Alexander; Alattar, Abdul Ghani; Karlsson, Henrik; Siva, Kavitha; Soneji, Shamit; Tedgård, Ulf; Chen, Jane-Jane; Gram, Magnus; Flygare, Johan

doi:10.1016/j.exphem.2021.10.005

Cited by 3 publications

(3 citation statements)

References 51 publications

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“…Future studies to elucidate the molecular mechanisms underlying hyporesponsiveness to Epo will be invaluable to our understanding of erythropoiesis in disease states such as iron deficiency anemia, hemoglobinopathies and anemia of inflammation. The recent discovery that ribosomal protein synthesis is regulated directly by HRI in addition to repression of mTORC1 [17 ▪▪ ] also support the role of HRI in the disorder of ribosomopathies such as Diamond-Blackfan anemia as recently reported [56 ▪▪ ].…”

Section: Discussionmentioning

confidence: 56%

Translational control by heme-regulated elF2α kinase during erythropoiesis

Chen

Zhang

2022

Current Opinion in Hematology

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Purpose of reviewHRI is the heme-regulated elF2α kinase that phosphorylates the α-subunit of elF2. Although the role of HRI in inhibiting globin synthesis in erythroid cells is well established, broader roles of HRI in translation have been uncovered recently. This review is to summarize the new discoveries of HRI in stress erythropoiesis and in fetal γ-globin expression.Recent findingsHRI and activating transcription factor 4 (ATF4) mRNAs are highly expressed in early erythroblasts. Inhibition of protein synthesis by HRI-phosphorylated elF2α (elF2αP) is necessary to maintain protein homeostasis in both the cytoplasm and mitochondria. In addition, HRI-elF2αP specifically enhances translation of ATF4 mRNA leading to the repression of mechanistic target of rapamycin complex 1 (mTORC1) signaling. ATF4-target genes are most highly activated during iron deficiency to maintain mitochondrial function, redox homeostasis, and to enable erythroid differentiation. HRI is therefore a master translation regulator of erythropoiesis sensing intracellular heme concentrations and oxidative stress for effective erythropoiesis. Intriguingly, HRI-elF2αP-ATF4 signaling also inhibits fetal hemoglobin production in human erythroid cells.SummaryThe primary function of HRI is to maintain protein homeostasis accompanied by the induction of ATF4 to mitigate stress. Role of HRI-ATF4 in γ-globin expression raises the potential of HRI as a therapeutic target for hemoglobinopathy.

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Section: Discussionmentioning

confidence: 56%

Translational control by heme-regulated elF2α kinase during erythropoiesis

Chen

Zhang

2022

Current Opinion in Hematology

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“…The protective effect observed on erythropoiesis can possibly be linked to the ability to mitigate intracellular heme toxicity. It is possible that radiation induces a block in the cap-dependent translation of globin mRNA [ 31 ] and leads to heme accumulation, analogous to ribosome deficiency causing erythroblast heme toxicity in Diamond–Blackfan anemia [ 32 ]. In addition, rA1M may have a more general, cell- and membrane-stabilizing effect on circulating cells, consistent with previous data indicating a role in RBC protection [ 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

Recombinant α1-Microglobulin (rA1M) Protects against Hematopoietic and Renal Toxicity, Alone and in Combination with Amino Acids, in a 177Lu-DOTATATE Mouse Radiation Model

et al. 2023

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177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) is used clinically to treat metastasized or unresectable neuroendocrine tumors (NETs). Although 177Lu-DOTATATE is mostly well tolerated in patients, bone marrow suppression and long-term renal toxicity are still side effects that should be considered. Amino acids are often used to minimize renal radiotoxicity, however, they are associated with nausea and vomiting in patients. α1-microglobulin (A1M) is an antioxidant with heme- and radical-scavenging abilities. A recombinant form (rA1M) has previously been shown to be renoprotective in preclinical models, including in PRRT-induced kidney damage. Here, we further investigated rA1M’s renal protective effect in a mouse 177Lu-DOTATATE model in terms of administration route and dosing regimen and as a combined therapy with amino acids (Vamin). Moreover, we investigated the protective effect of rA1M on peripheral blood and bone marrow cells, as well as circulatory biomarkers. Intravenous (i.v.) administration of rA1M reduced albuminuria levels and circulatory levels of the oxidative stress-related protein fibroblast growth factor-21 (FGF-21). Dual injections of rA1M (i.e., at 0 and 24 h post-177Lu-DOTATATE administration) preserved bone marrow cellularity and peripheral blood reticulocytes. Administration of Vamin, alone or in combination with rA1M, did not show any protection of bone marrow cellularity or peripheral reticulocytes. In conclusion, this study suggests that rA1M, administered i.v. for two consecutive days in conjunction with 177Lu-DOTATATE, may reduce hematopoietic and kidney toxicity during PRRT with 177Lu-DOTATATE.

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“…Moreover, since stress granules are induced by mTORC1 [ 61 ], we suggest that HRI activation may be a general nexus to coordinate survival adaptation to PIs by ATF4-dependent and independent mechanisms. We propose that inhibitors of HRI, which were originally designed for the treatment of certain types of anemia [ 62 ], should be considered as an adjuvant therapy to cancer.…”

Section: Discussionmentioning

confidence: 99%

An mTORC1 to HRI signaling axis promotes cytotoxicity of proteasome inhibitors in multiple myeloma

et al. 2022

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Multiple myeloma (MM) causes approximately 20% of deaths from blood cancers. Notwithstanding significant therapeutic progress, such as with proteasome inhibitors (PIs), MM remains incurable due to the development of resistance. mTORC1 is a key metabolic regulator, which frequently becomes dysregulated in cancer. While mTORC1 inhibitors reduce MM viability and synergize with other therapies in vitro, clinically, mTORC1 inhibitors are not effective for MM. Here we show that the inactivation of mTORC1 is an intrinsic response of MM to PI treatment. Genetically enforced hyperactivation of mTORC1 in MM was sufficient to compromise tumorigenicity in mice. In vitro, mTORC1-hyperactivated MM cells gained sensitivity to PIs and hypoxia. This was accompanied by increased mitochondrial stress and activation of the eIF2α kinase HRI, which initiates the integrated stress response. Deletion of HRI elevated the toxicity of PIs in wt and mTORC1-activated MM. Finally, we identified the drug PMA as a robust inducer of mTORC1 activity, which synergized with PIs in inducing MM cell death. These results help explain the clinical inefficacy of mTORC1 inhibitors in MM. Our data implicate mTORC1 induction and/or HRI inhibition as pharmacological strategies to enhance MM therapy by PIs.

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Targeting elevated heme levels to treat a mouse model for Diamond-Blackfan Anemia

Cited by 3 publications

References 51 publications

Translational control by heme-regulated elF2α kinase during erythropoiesis

Translational control by heme-regulated elF2α kinase during erythropoiesis

Recombinant α1-Microglobulin (rA1M) Protects against Hematopoietic and Renal Toxicity, Alone and in Combination with Amino Acids, in a 177Lu-DOTATATE Mouse Radiation Model

An mTORC1 to HRI signaling axis promotes cytotoxicity of proteasome inhibitors in multiple myeloma

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