RESUMO
The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management.
Assuntos
Mutação em Linhagem Germinativa , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenosina Desaminase/genética , Dineínas do Axonema/genética , Estudos de Coortes , Humanos , Degradação do RNAm Mediada por Códon sem Sentido , Linhagem , Perforina/genética , Glicoproteínas da Membrana de Plaquetas/genética , RNA Helicases/genética , Receptores de Interleucina-17/genética , Proteínas de Transporte Vesicular/genética , Sequenciamento do ExomaRESUMO
Non-myeloablative allogeneic hematopoietic cell transplantation (HCT) offers a potentially curative therapy for older patients with hematologic malignancies. However, the treatment modality is underutilized and, to date, there are only limited data on outcomes in people older than 60 years. This study describes the toxicities and outcomes of non-myeloablative allogeneic HCT, conditioned with low-dose total body irradiation with or without fludarabine, in patients aged 60-75 years enrolled in prospective multicenter clinical trials. Increasing age was not associated with adverse outcome. Relapse risk and comorbidity burden predicted survival; fit patients with low risk of disease relapse did well after transplant regardless of age. Despite demonstrating the feasibility of non-myeloablative allogeneic HCT in patients aged 60-75 years, the study raises important questions regarding how best to manage older patients with high-risk hematologic malignancies and how to optimize our approach to allogeneic HCT in this age group.
RESUMO
Recent studies have expanded our understanding of the role of the anti-inflammatory cytokine interleukin (IL)-10, produced by multiple lineages of both human and murine T cells, in regulating the immune response. Here, we demonstrate that the small percentage of circulating CD4(+) T cells that secrete IL-10 can be isolated from human peripheral blood and, importantly, we have optimized a protocol to expand these cells in both antigen-specific and polyclonal manners. Expanded CD4(+)IL-10(+) T cells abrogate proliferation and T helper (Th) 1-like cytokine production in an antigen-specific manner, and to a lesser extent exhibit bystander suppressive capacity. CD4(+)IL-10(+) T cells are suppressive in a cell contact-dependent way, though they do not require secretion of IL-10 for their suppressive role in vitro. CD4(+)IL-10(+) T cells have an activated phenotype, with high expression of CD25, CD69, and cytotoxic T-lymphocyte antigen-4, and are largely FoxP3 negative. This novel method for the isolation and expansion of suppressive IL-10-secreting T cells has important implications both for further research and clinical therapeutic development.
