SUMMARY B cell development is often depicted as a linear process initiating in the fetus and continuing postnatally. Using a PU.1 hypomorphic mouse model, we found that B-1 and B-2 lymphopoiesis occurred in distinct fetal and adult waves differentially dependent on the Sfpi1 14 kB upstream regulatory element. The initial wave of fetal B-1 development was absent in PU.1 hypomorphic mice, while subsequent fetal and adult waves emerged. In contrast, B-2 lymphopoiesis occurred in distinct fetal and adult waves. Whole transcriptome profiling of fetal and adult B cell progenitors supported the existence of three waves of B-1 and two waves of B-2 development, and revealed that the network of transcription factors governing B lineage specification and commitment was highly divergent between B-1 and B-2 progenitors. These findings support the view that the B-1 and B-2 lineages are distinct and provide a genetic basis for layering of immune system development.

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Until there are better guidelines on the best approaches to handle missing data, investigators should report how missing data were handled to increase the quality and transparency of orthopaedic database research. Readers of large database studies should note whether handling of missing data was addressed and consider potential bias with high rates or unspecified or weak methods for handling missing data.

The PU.1 transcription factor plays a critical role in the regulation of T cell development, so a report that it is dispensable for fetal thymopoiesis is puzzling. To understand this paradox, we examined the requirement for PU.1, encoded by , during fetal, neonatal, and adult thymopoiesis in a PU.1 hypomorphic mouse generated by deletion of the 14-kb upstream regulatory element and by analysis of patterns of gene expression in fetal and adult T cell progenitors. Our data demonstrate that the initiation of thymopoiesis during early gestation is less dependent on PU.1 compared with T cell differentiation in adults and that fetal T cell progenitors express lower levels of compared with their adult counterparts. We also show that expression of the core network of T lineage transcription factors regulated by PU.1 differs in fetal and adult T cell progenitors. In particular, PU.1-regulated genes that promote T cell differentiation are differentially expressed in fetal versus adult early T lineage progenitors. These results indicate that the transcriptional differences between the fetal and adult T cell developmental programs are driven in part by differential levels of PU.1 expression and that this likely underlies the differences in the properties of fetal and adult T cell progenitors.

B-1 and B-2 B cells derive from distinct progenitors that emerge in overlapping waves of development. The number of murine B-1 progenitors peaks during fetal development while B-2 B cell production predominates in adult bone marrow. Many genetic mutations that underlie B-acute lymphoblastic leukemia (B-ALL) occur in the fetus, at which time B-1 progenitor numbers are high. However, whether B-ALL can initiate in B-1 progenitors is unknown. We now report that BCR-ABL transformed murine B-1 progenitors can be B-ALL cells of origin and demonstrate that they initiate disease more rapidly than oncogene expressing B-2 progenitors. We further demonstrate that B-1 progenitors exhibit relative resistance to apoptosis and undergo significant growth following oncogene expression and propose that these properties underlie the accelerated kinetics with which they initiate leukemia. These results provide a developmental perspective on the origin of B-ALL and indicate B cell lineage as a factor influencing disease progression.

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Background and Objectives: While historically aggressive, some synovial sarcomas (SS) are clinically indolent. This study sought to determine whether SS grade predicts oncologic outcomes and whether Grade 1 disease might exist.Methods: Thirty-five cases from 2010 to 2019 were retrospectively reviewed.Clinicopathological data were analyzed and Kaplan-Meier assessed survival. Results:The median patient age was 37 years (interquartile range: 28-51.5). The local control rate was 74.3%, and recurrence-free survival (RFS) was worse in positive versus negative margin resections (p = 0.023). The incidence of metastasis was 21.9% (n = 7) at a median 31 ± 31.7 months, and metastasis-free survival was 50.0% in Grade 3 SS versus 86.5% in Grade 2 (p = 0.026). Among a theoretical Grade 1 group, the overall survival (OS) and RFS profiles were improved compared to Grade 2 and 3 SS, respectively (p = 0.014 and p = 0.030). The Grade 1 group had a 15.8% (n = 3) metastatic rate and 80% 10-year survival.Conclusions: Tumor grade appears to predict outcomes in SS. A theoretical Grade 1 group showed improved OS and RFS versus Grades 2 and 3 SS, with metastatic rates and long-term survival resembling the historical literature for other low-grade soft tissue sarcomas. Our group continues to support the French Federation of Cancer Centers diagnostic strategy and NCCN treatment guidelines for SS.