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Hematopoietic stem cell loss and hematopoietic failure in severe aplastic anemia is driven by macrophages and aberrant podoplanin expression.

ABSTRACT: Severe aplastic anemia (SAA) results from profound hematopoietic stem cell loss. T cells and interferon gamma (IFN?) have long been associated with SAA, yet the underlying mechanisms driving hematopoietic stem cell loss remain unknown. Using a mouse model of SAA, we demonstrate that IFN?-dependent hematopoietic stem cell loss required macrophages. IFN? was necessary for bone marrow macrophage persistence, despite loss of other myeloid cells and hematopoietic stem cells. Depleting macrophages or abrogating IFN? signaling specifically in macrophages did not impair T-cell activation or IFN? production in the bone marrow but rescued hematopoietic stem cells and reduced mortality. Thus, macrophages are not required for induction of IFN? in SAA and rather act as sensors of IFN?. Macrophage depletion rescued thrombocytopenia, increased bone marrow megakaryocytes, preserved platelet-primed stem cells, and increased the platelet-repopulating capacity of transplanted hematopoietic stem cells. In addition to the hematopoietic effects, SAA induced loss of non-hematopoietic stromal populations, including podoplanin-positive stromal cells. However, a subset of podoplanin-positive macrophages was increased during disease, and blockade of podoplanin in mice was sufficient to rescue disease. Our data further our understanding of disease pathogenesis, demonstrating a novel role for macrophages as sensors of IFN?, thus illustrating an important role for the microenvironment in the pathogenesis of SAA.

SUBMITTER: McCabe A

PROVIDER: S-EPMC6119154 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Hematopoietic stem cell loss and hematopoietic failure in severe aplastic anemia is driven by macrophages and aberrant podoplanin expression.

McCabe Amanda A Smith Julianne N P JNP Costello Angelica A Maloney Jackson J Katikaneni Divya D MacNamara Katherine C KC

Haematologica 20180517 9

Severe aplastic anemia (SAA) results from profound hematopoietic stem cell loss. T cells and interferon gamma (IFNγ) have long been associated with SAA, yet the underlying mechanisms driving hematopoietic stem cell loss remain unknown. Using a mouse model of SAA, we demonstrate that IFNγ-dependent hematopoietic stem cell loss required macrophages. IFNγ was necessary for bone marrow macrophage persistence, despite loss of other myeloid cells and hematopoietic stem cells. Depleting macrophages or ...[more]

PMID: 29773597

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Project description:IMPORTANCE:Telomeres protect chromosome ends and are markers of cellular aging and replicative capacity. OBJECTIVE:To evaluate the association between recipient and donor pretransplant leukocyte telomere length with outcomes after unrelated donor allogeneic hematopoietic cell transplantation (HCT) for patients with severe aplastic anemia. DESIGN, PARTICIPANTS, AND SETTING:The study included 330 patients (235 acquired, 85 Fanconi anemia, and 10 Diamond-Blackfan anemia) and their unrelated donors who had pre-HCT blood samples and clinical and outcome data available at the Center for International Blood and Marrow Transplant Research. Patients underwent HCT between 1989 and 2007 in 84 centers and were followed-up to March 2013. EXPOSURES:Recipient and donor pre-HCT leukocyte telomere length classified into long (third tertile) and short (first and second tertiles combined) based on donor telomere length distribution. MAIN OUTCOMES AND MEASURES:Overall survival, neutrophil recovery, and acute and chronic graft-vs-host disease, as ascertained by transplant centers through regular patient follow-up. RESULTS:Longer donor leukocyte telomere length was associated with higher survival probability (5-year overall survival, 56%; number at risk, 57; cumulative deaths, 50) than shorter donor leukocyte telomere length (5-year overall survival, 40%; number at risk, 71; cumulative deaths, 128; P?=?.009). The association remained statistically significant after adjusting for donor age, disease subtype, Karnofsky performance score, graft type, HLA matching, prior aplastic anemia therapy, race/ethnicity, and calendar year of transplant (hazard ratio [HR], 0.61; 95% CI, 0.44-0.86). Similar results were noted in analyses stratified on severe aplastic anemia subtype, recipient age, HLA matching, calendar year of transplant, and conditioning regimen. There was no association between donor telomere length and neutrophil engraftment at 28 days (cumulative incidence, 86% vs 85%; HR, 0.94; 95% CI, 0.73-1.22), acute graft-vs-host disease grades III-IV at 100 days (cumulative incidence, 22% vs 28%; HR, 0.77; 95% CI, 0.48-1.23), or chronic graft-vs-host disease at 1-year (cumulative incidence, 28% vs 30%; HR, 0.81; 95% CI, 0.53-1.24) for long vs short, respectively. Pretransplant leukocyte telomere length in the recipients was not associated with posttransplant survival (HR, 0.91; 95% CI, 0.64-1.30). CONCLUSIONS AND RELEVANCE:Longer donor leukocyte telomere length was associated with increased 5-year survival in patients who received HCT for severe aplastic anemia. Patient leukocyte telomere length was not associated with survival. The results of this observational study suggest that donor leukocyte telomere length may have a role in long-term posttransplant survival.

Project description:CONTEXT:Critically short telomeres produce apoptosis, cell senescence, and chromosomal instability in tissue culture and animal models. Variations in telomere length have been reported in severe aplastic anemia but their clinical significance is unknown. OBJECTIVE:To investigate the relationship between telomere length and clinical outcomes in severe aplastic anemia. DESIGN, SETTING, AND PATIENTS:Single institution analysis of 183 patients with severe aplastic anemia who were treated in sequential prospective protocols at the National Institutes of Health from 2000 to 2008. The pretreatment leukocyte age-adjusted telomere length of patients with severe aplastic anemia consecutively enrolled in immunosuppression protocols with antithymocyte globulin plus cyclosporine for correlation with clinical outcomes were analyzed. MAIN OUTCOME MEASURES:Hematologic response, relapse, clonal evolution, and survival. RESULTS:There was no relationship between hematologic response and telomere length with response rates of 56.5% of 46 patients in the first, 54.3% of 46 in the second, 60% of 45 in the third, and 56.5% of 46 in the fourth quartiles. Multivariate analysis demonstrated that telomere length was associated with relapse, clonal evolution, and mortality. Evaluated as a continuous variable, telomere length inversely correlated with the probability of hematologic relapse (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.03-0.69; P = .01). The probability of clonal evolution was higher in patients in the first quartile (24.5%; 95% CI, 8.7%-37.5%) than in quartiles 2 through 4 (8.4%; 95% CI, 3.2%-13.3%; P = .009), and evolution to monosomy 7 or complex cytogenetics was more common in the first quartile (18.8%; 95% CI, 3.5%-31.6%) [corrected] than in quartiles 2 through 4 (4.5%; 95% CI, 0.5%-8.2%; P = .002) [corrected]. Survival between these 2 groups differed, with 66% (95% CI, 52.9%-82.5%) surviving 6 years in the first quartile compared with 83.8% (95% CI, 77.3%-90.9%) in quartiles 2 through 4 (P = .008). CONCLUSION:In a cohort of patients with severe aplastic anemia receiving immunosuppressive therapy, telomere length was unrelated to response but was associated with risk of relapse, clonal evolution, and overall survival.

Dataset Information

Hematopoietic stem cell loss and hematopoietic failure in severe aplastic anemia is driven by macrophages and aberrant podoplanin expression.

Publications

Hematopoietic stem cell loss and hematopoietic failure in severe aplastic anemia is driven by macrophages and aberrant podoplanin expression.

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