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

Horio, Tomohiro; Morishita, Eriko; Mizuno, Shohei; Uchino, Kaori; Hanamura, Ichiro; Espinoza, J. Luis; Morishima, Yasuo; Kodera, Yoshihisa; Onizuka, Makoto; Kashiwase, Koichi; Fukuda, Takahiro; Doki, Noriko; Miyamura, Koichi; Mori, Takehiko; Nakao, Shinji; Takami, Akiyoshi

doi:10.3390/cancers12020424

Cited by 10 publications

(5 citation statements)

References 56 publications

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“…The A allele has been associated with higher HO-1 expression levels than the T allele. The donor HO-1 genotype showed no effects on GVHD ( 54 ). This apparent discrepancy might be explained by the use of different genotyping methodologies (SNP versus (GT) n polymorphism) and we did not assess the incidence of overall survival, non-relapse mortality, and GVHD relapse-free survival.…”

Section: Discussionmentioning

confidence: 98%

Donor-Derived Myeloid Heme Oxygenase-1 Controls the Development of Graft-Versus-Host Disease

et al. 2021

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Graft-versus-host disease (GVHD) remains a major clinical drawback of allogeneic hematopoietic stem cell transplantation (HSCT). Here, we investigated how the stress responsive heme catabolizing enzyme heme oxygenase-1 (HO-1, encoded by HMOX1) regulates GVHD in response to allogeneic hematopoietic stem cell transplantation in mice and humans. We found that deletion of the Hmox1 allele, specifically in the myeloid compartment of mouse donor bone marrow, promotes the development of aggressive GVHD after allogeneic transplantation. The mechanism driving GVHD in mice transplanted with allogeneic bone marrow lacking HO-1 expression in the myeloid compartment involves enhanced T cell alloreactivity. The clinical relevance of these observations was validated in two independent cohorts of HSCT patients. Individuals transplanted with hematopoietic stem cells from donors carrying a long homozygous (GT)n repeat polymorphism (L/L) in the HMOX1 promoter, which is associated with lower HO-1 expression, were at higher risk of developing severe acute GVHD as compared to donors carrying a short (GT)n repeat (S/L or S/S) polymorphism associated with higher HO-1 expression. In this study, we showed the unique importance of donor-derived myeloid HO-1 in the prevention of lethal experimental GVHD and we corroborated this observation by demonstrating the association between human HMOX1 (GT)n microsatellite polymorphisms and the incidence of severe acute GVHD in two independent HSCT patient cohorts. Donor-derived myeloid HO-1 constitutes a potential therapeutic target for HSCT patients and large-scale prospective studies in HSCT patients are necessary to validate the HO-1 L/L genotype as an independent risk factor for developing severe acute GVHD.

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Section: Discussionmentioning

confidence: 98%

Donor-Derived Myeloid Heme Oxygenase-1 Controls the Development of Graft-Versus-Host Disease

et al. 2021

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“…Moreover, the SNP rs2071746 (−413A > T) polymorphism can also modulate HO-1 inducibility, being the higher HO-1 expression associated with the 413-A variant [ 57 ]. This polymorphism correlates with a reduced incidence of ischemic heart disease [ 58 ] and with graft survival after liver transplantation when present in the donor [ 59 ].…”

Section: Ho-1 Gene Transcription and Protein Localizationmentioning

confidence: 99%

Clinical Significance of Heme Oxygenase 1 in Tumor Progression

et al. 2021

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Heme oxygenase 1 (HO-1) plays a key role in cell adaptation to stressors through the antioxidant, antiapoptotic, and anti-inflammatory properties of its metabolic products. For these reasons, in cancer cells, HO-1 can favor aggressiveness and resistance to therapies, leading to poor prognosis/outcome. Genetic polymorphisms of HO-1 promoter have been associated with an increased risk of cancer progression and a high degree of therapy failure. Moreover, evidence from cancer biopsies highlights the possible correlation between HO-1 expression, pathological features, and clinical outcome. Indeed, high levels of HO-1 in tumor specimens often correlate with reduced survival rates. Furthermore, HO-1 modulation has been proposed in order to improve the efficacy of antitumor therapies. However, contrasting evidence on the role of HO-1 in tumor biology has been reported. This review focuses on the role of HO-1 as a promising biomarker of cancer progression; understanding the correlation between HO-1 and clinical data might guide the therapeutic choice and improve the outcome of patients in terms of prognosis and life quality.

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“…HLA genes are encoded in a segment on human chromosome 6p21.3 (the most variable region in the human genome) which has products that are involved in antigen presentation to CD8+ T cells, natural killer cells (NK cells), and CD4+ T cells and are crucial for enabling the immune system to recognize "self" versus "non-self" antigens [43]. Furthermore, using gene association studies, we and others have identified genetic variants in genes located outside the HLA region (non-HLA variants), especially single nucleotide polymorphisms (SNPs) in genes which have products that are associated with the immune response implicated in transplant outcomes [44][45][46][47][48].…”

Section: Role Of Nlrp3 In the Development Of Gvhdmentioning

confidence: 99%

The Impact of NLRP3 Activation on Hematopoietic Stem Cell Transplantation

Espinoza

Kamio

Lam

et al. 2021

IJMS

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NLR family pyrin domain-containing 3 (NLRP3) is an intracellular protein that after recognizing a broad spectrum of stressors, such as microbial motifs and endogenous danger signals, promotes the activation and release of the pro-inflammatory cytokines IL-1β and IL-18, thus playing an essential role in the innate immune response. Several blood cell types, including macrophages, dendritic cells, and hematopoietic stem and progenitor cells (HSPCs), express NLRP3, where it has been implicated in various physiological and pathological processes. For example, NLRP3 participates in the development and expansion of HSPCs, and their release from bone marrow into the peripheral blood has been implicated in certain hematological disorders including various types of leukemia. In addition, accumulating evidence indicates that activation of NLRP3 plays a pivotal role in the development of transplant complications in patients receiving hematopoietic stem cell transplantation (HSCT) including graft versus host disease, severe infections, and transplant-related mortality. The majority of these complications are triggered by the severe tissue damage derived from the conditioning regimens utilized in HSCT which, in turn, activates NLRP3 and, ultimately, promotes the release of proinflammatory cytokines such as IL-1β and IL-18. Here, we summarize the implications of NLRP3 in HSCT with an emphasis on the involvement of this inflammasome component in transplant complications.

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

Cited by 10 publications

References 56 publications

Donor-Derived Myeloid Heme Oxygenase-1 Controls the Development of Graft-Versus-Host Disease

Donor-Derived Myeloid Heme Oxygenase-1 Controls the Development of Graft-Versus-Host Disease

Clinical Significance of Heme Oxygenase 1 in Tumor Progression

The Impact of NLRP3 Activation on Hematopoietic Stem Cell Transplantation

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