Heme oxygenase-1: A new druggable target in the management of chronic and acute myeloid leukemia

Salerno, Loredana; Romeo, Giuseppe; Modica, Maria; Amata, Emanuele; Sorrenti, Valeria; Barbagallo, Ignazio; Pittalà, Valeria

doi:10.1016/j.ejmech.2017.07.031

Cited by 54 publications

(34 citation statements)

References 144 publications

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“…Recent reports [35][36][37] have suggested that the overexpression of HO-1 may promote the progression and relapse of various blood cancers, especially CML, as well as carcinogenesis, progression, and resistance to therapy in solid cancers. Unlike these observations, in the present study, the donor HO-1 A/A or A/T genotype (plausibly associated with the higher inducibility of HO-1) was associated with better survival outcomes without increasing the risk of disease relapse after allo-HSCT in patients with high-risk patients.…”

Section: Discussionmentioning

confidence: 99%

Donor Heme Oxygenase-1 Promoter Gene Polymorphism Predicts Survival after Unrelated Bone Marrow Transplantation for High-Risk Patients

Horio

Morishita

Mizuno

et al. 2020

Cancers

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Heme oxygenase-1 (HO-1), an intracellular enzyme that catalyzes the degradation of heme into biliverdin, free iron, and carbon monoxide, exerts anti-inflammatory and cytoprotective effects against endothelial cell injury. The HO-1 promoter gene has one important single-nucleotide polymorphism (SNP) rs2071746 (-413A>T) that is functional, and the A allele has been reported to be associated with higher HO-1 expression levels than the T allele. We investigated the influence of the HO-1 rs2071746 SNP on the transplant outcomes in 593 patients with hematological malignancies undergoing unrelated, human leukocyte antigen (HLA)-matched, T-cell-replete bone marrow transplantation (BMT) through the Japan Donor Marrow Program. In patients with high-risk diseases, the donor A/A or A/T genotype was associated with better 5 year overall survival (35% vs. 25%; p = 0.03) and 5 year disease-free survival (35% vs. 22%; p = 0.0072), compared to the donor T/T genotype. These effects were not observed in patients with low-risk diseases. The current findings therefore indicate that HO-1 rs2071746 genotyping could be useful for selecting donors and tailoring transplant strategies for patients with high-risk hematologic malignancies.

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Section: Discussionmentioning

confidence: 99%

Donor Heme Oxygenase-1 Promoter Gene Polymorphism Predicts Survival after Unrelated Bone Marrow Transplantation for High-Risk Patients

Horio

Morishita

Mizuno

et al. 2020

Cancers

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“…This study provides deeper insight into the regulatory effect of heme and might aid in unraveling the role of heme in JAK2-related diseases. Especially in myeloid leukemia, the heme-degrading enzyme heme oxygenase 1 has recently been identified as druggable target (38). Consequently, localizing heme-binding sites may aid in the development of novel research tools and subsequently new targeted drugs.…”

Section: Discussionmentioning

confidence: 99%

Structural insights into the interaction of heme with protein tyrosine kinase JAK2

Schmalohr

Mustafa

Krämer

et al. 2020

Preprint

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Janus kinase 2 (JAK2) is the most important signal transducing tyrosine kinase in erythropoietic precursor cells. Its malfunction drives several myeloproliferative disorders. Heme is a small metal ion-carrying molecule, which is incorporated into hemoglobin in erythroid precursor cells to transport oxygen. In addition, heme is a signaling molecule and regulator of various biochemical processes. Here we show that heme exposure leads to hyperphosphorylation of JAK2 in a myeloid cancer cell line. Two peptides identified in JAK2 represent heme-regulatory motifs and show low micromolar affinities for heme. These peptides map to the kinase domain of JAK2, which is essential for downstream signaling. We suggest these motifs to be the interaction sites of heme with JAK2, which drive the heme-induced hyperphosphorylation. The results presented herein may facilitate the development of heme-related pharmacological tools to combat myeloproliferative disorders.

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“…It is likely that CK2 is also required for the FGF2-induced HO-1 upregulation in Dox-treated cardiomyocytes (Koleini et al 2017). Catabolic end-products elicited by the action of HO-1 exert “antioxidant, anti-apoptotic, and immune-modulating effects, leading to overall cytoprotective and beneficial functions” (Salerno et al 2017) for non-malignant tissues. On the other hand, in the case of cancer, HO-1 is pro-tumorigenic and causes resistance to anti-cancer drug treatments; inhibition or modulation of HO-1-generating pathways is beneficial in the treatment of leukemia (Salerno et al 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Catabolic end-products elicited by the action of HO-1 exert “antioxidant, anti-apoptotic, and immune-modulating effects, leading to overall cytoprotective and beneficial functions” (Salerno et al 2017) for non-malignant tissues. On the other hand, in the case of cancer, HO-1 is pro-tumorigenic and causes resistance to anti-cancer drug treatments; inhibition or modulation of HO-1-generating pathways is beneficial in the treatment of leukemia (Salerno et al 2017). As we showed here, S117A-FGF2 did not upregulate HO-1 and its ability for acute cardiomyocyte protection against Dox was not blocked by HO-1 inhibition.…”

Section: Discussionmentioning

confidence: 99%

Non-mitogenic FGF2 protects cardiomyocytes from acute doxorubicin-induced toxicity independently of the protein kinase CK2/heme oxygenase-1 pathway

et al. 2018

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Doxorubicin (Dox)-induced cardiotoxicity, a limiting factor in the use of Dox to treat cancer, can be mitigated by the mitogenic factor FGF2 in vitro, via a heme oxygenase 1 (HO-1)-dependent pathway. HO-1 upregulation was reported to require protein kinase CK2 activity. We show that a mutant non-mitogenic FGF2 (S117A-FGF2), which does not activate CK2, is cardioprotective against acute cardiac ischemic injury. We now investigate the potential of S117A-FGF2 to protect cardiomyocytes against acute Dox injury and decrease Dox-induced upregulation of oxidized phospholipids. The roles of CK2 and HO-1 in cardiomyocyte protection are also addressed.Rat neonatal cardiomyocyte cultures were used as an established in vitro model of acute Dox toxicity. Pretreatment with S117A-FGF2 protected against Dox-induced: oxidative stress; upregulation of fragmented and non-fragmented oxidized phosphatidylcholine species, measured by LC/MS/MS; and cardiomyocyte injury and cell death measured by LDH release and a live-dead assay. CK2 inhibitors (TBB and Ellagic acid), did not affect protection by S117A-FGF2 but prevented protection by mitogenic FGF2. Furthermore, protection by S117A-FGF2, unlike that of FGF2, was not prevented by HO-1 inhibitors and S117A-FGF2 did not upregulate HO-1. Protection by S117A-FGF2 required the activity of FGF receptor 1 and ERK.We conclude that mitogenic and non-mitogenic FGF2 protect from acute Dox toxicity by common (FGFR1) and distinct, CK2/HO-1- dependent or CK2/HO-1-independent (respectively), pathways. Non-mitogenic FGF2 merits further consideration as a preventative treatment against Dox cardiotoxicity.

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Heme oxygenase-1: A new druggable target in the management of chronic and acute myeloid leukemia

Cited by 54 publications

References 144 publications

Donor Heme Oxygenase-1 Promoter Gene Polymorphism Predicts Survival after Unrelated Bone Marrow Transplantation for High-Risk Patients

Donor Heme Oxygenase-1 Promoter Gene Polymorphism Predicts Survival after Unrelated Bone Marrow Transplantation for High-Risk Patients

Structural insights into the interaction of heme with protein tyrosine kinase JAK2

Non-mitogenic FGF2 protects cardiomyocytes from acute doxorubicin-induced toxicity independently of the protein kinase CK2/heme oxygenase-1 pathway

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