Interactions between leukemic niche and HSPCs identify a novel signaling axis
Wu L, Amarachintha S , Xu J, et al. Mesenchymal COX2-PG Secretome Engages NR4A-WNT Signalling Axis in Haematopoietic Progenitors to Suppress Anti-Leukaemia Immunity. British Journal of Haematology. 2018 on-line library doi: 10.1111/bjh.15548.
Study results suggest that specific interactions between leukaemic mesenchymal niche and haematopoietic stem and progenitor cells (HSPCs) orchestrate a unique COX2/PG-NR4A/WNT signaling axis, connecting inflammation, cellular metabolism, and cancer immunity. Researchers studied the interaction between leukaemic mesenchymal niche and HSPCs using the model of Fanconi anaemia (FA), a genetic disorder marked by bone marrow failure and leukaemia. Untargeted metabolomics analysis revealed progressively elevated prostaglandins (PGs) in the mesenchymal stromal cells (MSCs) of FA patients with myelodysplastic syndromes and acute myeloid leukaemia (AML). Reduced secretion of PGs subsequent to inflammatory cyclooxygenase 2 (COX2) inhibition ameliorated HSPC/myeloid expansion. COX2 inhibition resulted in significantly decreased NR4A transcription factors and WNT signaling genes expression. Mechanistically, NR4A1 and NR4A2 synergistically activate the CTNNB1 gene promoter; and knocking down CTNNB1 or NR4A1 in AML-MSC-co-cultured-CD34+ cells increased production of leukaemia-reactive T-effector cells and restored anti-leukaemia immunity.
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Bone Marrow Resident Macrophages Essential for Engraftment
Kaur S, Raggatt LJ, Millard SM, et al. Self-Repopulating Recipient Bone Marrow Resident Macrophages Promote Long-Term Hematopoietic Stem Cell Engraftment. Blood. 2018; 132 (7): 735.
Research suggests that recipient bone marrow resident macrophages are important for optimal outcomes following hematopoietic stem cell transplantation and could be an important consideration in the development of pre-procedure conditioning therapies and/or chemoresistance strategies. Researchers used a myeloid reporter gene to dissect the persistence of bone marrow and splenic macrophage subsets following lethal irradiation and autologous hematopoietic stem cell transplantation in an animal model. Multiple subsets survived after autologous hematopoietic stem cell transplantation with organ-specific persistence kinetics. In bone marrow, radiation-resistant recipient CD169+ resident macrophages and erythroid-island macrophages self-repopulated long-term after transplantation via autonomous cell division. Post-transplant peak expansion of recipient CD169+ resident macrophage number in bone marrow promoted persistent engraftment of phenotypic long-term reconstituting hematopoietic stem cells within bone marrow. Targeted depletion of recipient CD169+ macrophages significantly compromised long-term bone marrow engraftment of hematopoietic stem cells and consequently impaired hematopoietic reconstitution.
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In Silico Predicted Nonpermissive HLA-DPB1 Mismatches
Arrieta-Bolaños E, Crivello P, Shaw BE, et al. In Silico Prediction of Nonpermissive HLA-DPB1 Mismatches in Unrelated HCT by Functional Distance. Blood Advances. 2018; 2 (14): 1773.
Researchers have demonstrated that nonpermisive HLA mismatches between hematopoetic cell transplantation (HCT) recipients and donors, which influence alloreactivity and affect procedure outcomes, can be predicted in silico using a functional distance (FD) scoring system. Until now, nonpermissive T-cell epitope (TCE) group mismatches have been defined by alloreactive T-cell cross-reactivity (TCE-X) for 52/80 human leukocyte antigen (HLA)-DPB1 alleles. The new TCE-FD system, by comparison, is based on the median impact of exon 2-encoded amino acid polymorphism on T-cell alloreactivity and is designed to capture all 80 alleles. Using data from the Center for International Blood and Marrow Transplant Research, the investigators compared clinical outcomes from TCE-X and TCE-FD after 8/8 HLA-matched unrelated donor HCTs on 2,730 patients with acute leukemia, myelodysplastic syndrome, and chronic myelogenous leukemia. Both of the models, which agreed 92.3% of the time, associated nonpermissive mismatches with lower rates of overall survival and higher rates of transplant-related mortality and also acute and chronic graft-versus-host disease. The findings could inform unrelated donor searches going forward as well as open new avenues for developing HLA risk-prediction models in HCT.
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