ABSTRACT
The origin and specification of human dendritic cells (DCs) have not been investigated at the clonal level. Through the use of clonal assays, combined with statistical computation, to quantify the yield of granulocytes, monocytes, lymphocytes and three subsets of DCs from single human CD34+ progenitor cells, we found that specification to the DC lineage occurred in parallel with specification of hematopoietic stem cells (HSCs) to the myeloid and lymphoid lineages. This started as a lineage bias defined by specific transcriptional programs that correlated with the combinatorial 'dose' of the transcription factors IRF8 and PU.1, which was transmitted to most progeny cells and was reinforced by upregulation of IRF8 expression driven by the hematopoietic cytokine FLT3L during cell division. We propose a model in which specification to the DC lineage is driven by parallel and inheritable transcriptional programs in HSCs and is reinforced over cell division by recursive interactions between transcriptional programs and extrinsic signals.
Subject(s)
Cell Lineage , Dendritic Cells/cytology , Hematopoietic Stem Cells/cytology , Interferon Regulatory Factors/metabolism , Leukopoiesis , Multipotent Stem Cells/cytology , Animals , Cell Differentiation , Fetal Blood , Flow Cytometry , Humans , Interferon Regulatory Factors/genetics , Mice , Mice, Inbred NOD , Mice, Knockout , Principal Component Analysis , Proto-Oncogene Proteins/metabolism , Trans-Activators/metabolism , Up-RegulationABSTRACT
De novo CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is a subtype of DLBCL found predominantly in older individuals. This particular subtype has been associated with a female predominance and a more aggressive clinical course. Conversely, this entity has not been described in the pediatric population. We report a case of a 12 year-old boy who presented with an ileocecal intussusception. Radiologic, morphologic, and immunophenotypic analysis revealed an isolated extranodal mass consistent with a CD5+ DLBCL, germinal center cell phenotype. Fluorescent in situ hybridization analysis was negative for cMYC, BCL6, BCL2, MLL, and IGH/CCND1 rearrangement and showed loss of one copy of MLL in 32% cells. The patient was treated with four cycles of cyclophosphamide, vincristine, prednisolone, methotrexate, and doxorubicin and achieved complete remission. To the best of our knowledge, this is the first detailed report of a de novo CD5+ DLBCL occurring in a child.
