European journal of haematology
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Pembrolizumab is a humanized monoclonal antibody directed against programmed cell death protein 1 (PD-1), a key immune-inhibitory molecule expressed on T cells and implicated in CD4+ T-cell exhaustion and tumor immune-escape mechanisms. Classical Hodgkin's lymphoma (cHL) is a unique B-cell malignancy in the sense that malignant Reed-Sternberg (RS) cells represent a small percentage of cells within an extensive immune cell infiltrate. ⋯ By augmenting antitumor immune response, pembrolizumab and nivolumab, another monoclonal antibody against PD-1, have shown significant activity in patients with relapsed/refractory cHL as well as an acceptable toxicity profile with immune-related adverse events that are generally manageable. In this review, we explore the rationale for targeting PD-1 in cHL, review the clinical trial results supporting the use of checkpoint inhibitors in this disease, and present future directions for investigation in which this approach may be used.
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Heterozygous mutations in the transcriptional regulator GATA-2 associate with multilineage immunodeficiency, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML). The majority of these mutations localize in the zinc finger (ZnF) domains, which mediate GATA-2 DNA binding. Deregulated hematopoiesis with GATA-2 mutation frequently develops in adulthood, yet GATA-2 function in the bone marrow remains unresolved. ⋯ Moreover, myeloid lineage populations were particularly sensitive to Gata2 hemizygosity, while molecular assays indicated GATA-2 regulates c-Kit expression in multilineage progenitor cells. Enforced c-Kit expression in Gata2 C-ZnF-deficient hematopoietic progenitors enhanced myeloid colony activity, suggesting GATA-2 sustains myelopoiesis via a cell intrinsic role involving maintenance of c-Kit expression. Our results provide insight into mechanisms regulating hematopoiesis in bone marrow and may contribute to a better understanding of immunodeficiency and bone marrow failure associated with GATA-2 mutation.