ABSTRACT
Mature lymphoid cells express the transcription repressor Bach2, which imposes regulation on humoral and cellular immunity. Here we found critical roles for Bach2 in the development of cells of the B lineage, commencing from the common lymphoid progenitor (CLP) stage, with Bach1 as an auxiliary. Overexpression of Bach2 in pre-pro-B cells deficient in the transcription factor EBF1 and single-cell analysis of CLPs revealed that Bach2 and Bach1 repressed the expression of genes important for myeloid cells ('myeloid genes'). Bach2 and Bach1 bound to presumptive regulatory regions of the myeloid genes. Bach2(hi) CLPs showed resistance to myeloid differentiation even when cultured under myeloid conditions. Our results suggest that Bach2 functions with Bach1 and EBF1 to promote B cell development by repressing myeloid genes in CLPs.
Subject(s)
B-Lymphocytes/cytology , Basic-Leucine Zipper Transcription Factors/metabolism , Cell Differentiation/physiology , Precursor Cells, B-Lymphoid/cytology , Trans-Activators/metabolism , Animals , B-Lymphocytes/metabolism , Basic-Leucine Zipper Transcription Factors/genetics , Cell Lineage , Cell Separation , Chromatin Immunoprecipitation , Electrophoretic Mobility Shift Assay , Flow Cytometry , Gene Expression Regulation/physiology , Lymphoid Progenitor Cells/cytology , Lymphoid Progenitor Cells/metabolism , Lymphopoiesis/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Oligonucleotide Array Sequence Analysis , Precursor Cells, B-Lymphoid/metabolism , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Trans-Activators/geneticsABSTRACT
It is difficult to predict the efficacy of deferasirox (DFX) as its pharmacokinetics varies among patients. The area under the curve (AUC) is reportedly useful for determining adequate DFX dosage; however, serum concentration measurements are often challenging. Effective DFX dosage is thus defined by assessing the efficacy of this agent in clinical practice. To analyze a predictive response marker to DFX therapy for use in adjusting the effective dosage during the early treatment phase, we retrospectively evaluated 39 DFX-treated patients. We defined response as a >40 % decrease in serum ferritin concentration from the pretreatment level. A maximum elevation of the total iron-binding capacity (TIBC) correlated with response in a multivariate analysis of iron metabolic markers (R (2) = 0.37, p < 0.001). A receiver operating characteristic curve analysis revealed that TIBC elevation had an AUC of 0.85 (p < 0.001) and the optimal cut-off value of TIBC elevation was 150 µg/dl. TIBC elevation of >150 µg/dl is a favorable predictor of effective ferritin reduction in DFX therapy (hazard ratio 29.6, 95 % confidence interval 4.8-183.6; p < 0.001). DFX therapy with TIBC monitoring may enable the determination of the minimum effective DFX dosage.
Subject(s)
Benzoates/therapeutic use , Blood Proteins/metabolism , Ferritins/blood , Iron Chelating Agents/therapeutic use , Iron Overload/drug therapy , Iron/blood , Triazoles/therapeutic use , Deferasirox , Drug Monitoring , Female , Hematologic Neoplasms/blood , Hematologic Neoplasms/pathology , Hematologic Neoplasms/therapy , Humans , Iron Overload/blood , Iron Overload/etiology , Iron Overload/pathology , Male , Middle Aged , Multivariate Analysis , Prognosis , Protein Binding , ROC Curve , Retrospective Studies , Transfusion Reaction , Treatment OutcomeABSTRACT
Bacteremia due to Mycobacterium massiliense is rare. We present here the case of a 58-year-old man with chronic myelogenous leukemia complicated by bacteremia caused by M. massiliense. The microorganisms were identified as M. massiliense by sequencing analysis, having initially been misdiagnosed as M. abscessus by DNA-DNA hybridization.
