Article

The Protean Nature of Cells in the B Lymphocyte Lineage

The Division of Basic Sciences, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Immunity (Impact Factor: 21.56). 07/2007; 26(6):703-14. DOI: 10.1016/j.immuni.2007.05.013
Source: PubMed

ABSTRACT

The subdivision of bone marrow (BM) with surface markers and reporter systems and the use of multiple culture and transplantation assays to assess differentiation potential have led to extraordinary progress in defining stages of B lymphopoiesis between the hematopoietic stem cell and B cell receptor (BCR)-expressing lymphocytes. Despite the lack of standard nomenclature and a series of technical issues that still need to be resolved, there seems to be a general consensus regarding the major route to becoming a B cell. Nevertheless, evidence that additional, minor pathways through which B lineage cells are generated exists, and a new appreciation that lymphoid progenitors are protean and able to alter their differentiation potential during embryogenesis and after birth in response to infections suggests that a full understanding of B cell development and how it is regulated has not yet been attained.

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    • "Stages shown include those analyzed in Seita et al. [1]. Pluripotent hematopoietic stem cells (HSC) differentiate in the bone marrow to generate multipotent progenitors (MPP), common lymphoid progenitors (CLP), B lymphoid progenitors (BLP), pre–pro-B cells, and B cell fractions as defined previously by Hardy and colleagues [2]. Although not indicated, lymphoid-primed multipotent progenitors (LMPP) would be present between MPP and CLP. "
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    ABSTRACT: The systematic activation of the B cell–specific transcriptional network drives differentiation of hematopoietic stem cells through B lymphopoiesis. This process requires the ordered expression of the following transcription factors: PU.1, Ikaros, E2A, Stat5, EBF1, Foxo1, and Pax5. Collectively, PU.1, Ikaros and E2A orchestrate early modifications of lineage-specific genes (lineage priming) necessary for the development of all lymphoid cells. Initiation of B lineage specification and commitment requires responsiveness to interleukin-7 mediated by Stat5. E2A, EBF1 and Foxo1 function in concert to activate early genes of the B cell–specific program, V(D)J recombination, and expression of Pax5. Pax5 synergizes with these factors and promotes locus contraction necessary for V(D)J recombination. Together, EBF1 and Pax5 mediate B cell lineage commitment via repression of genes of other hematopoietic lineages. Here, we describe the global network of regulatory circuits and epigenetic mechanisms that initiate and drive early B cell development.
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    • "In particular, B-lymphopoiesis has been characterised in great detail thanks to the identification of a wealth of molecular and genetic markers that have allowed for the accurate definition of the individual stages of development of the mature B-cell phenotype123. The B-lymphoid commitment of multipotent haematopoietic progenitors, as well as their progressive lineage restriction, that is, the stepwise acquisition of B-lymphoid features and the parallel loss of alternative developmental potential, is tightly controlled by the concerted action of a complex network of transcriptional and/or epigenetic regulators[2,4567891011121314151617. Among these, early Bcell factor 1 (EBF1) is regarded as a master determinant of the specification, development, and maintenance of the Blymphoid lineage[18]. "
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    ABSTRACT: The development of the B-lymphoid cell lineage is tightly controlled by the concerted action of a network of transcriptional and epigenetic regulators. EBF1, a central component of this network, is essential for B-lymphoid specification and commitment as well as for the maintenance of the B-cell identity. Genetic alterations causing loss of function of these B-lymphopoiesis regulators have been implicated in the pathogenesis of B-lymphoid malignancies, with particular regard to B-cell acute lymphoblastic leukaemias (B-ALLs), where their presence is frequently detected. The activity of the B-cell regulatory network may also be disrupted by the aberrant expression of inhibitory molecules. In particular, two multi-zinc finger transcription cofactors named ZNF423 and ZNF521 have been characterised as potent inhibitors of EBF1 and are emerging as potentially relevant contributors to the development of B-cell leukaemias. Here we will briefly review the current knowledge of these factors and discuss the importance of their functional cross talk with EBF1 in the development of B-cell malignancies.
    Full-text · Article · Dec 2015
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    • "B cells at various stages of development may also be phenotyped based on the expression of specific surface markers [69], [70]. dCK KO mice have a partial block at the pro-B (CD43+CD19+) to pre-B cell (CD43−CD19+) transition [36]. "
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    ABSTRACT: Efficient and adequate generation of deoxyribonucleotides is critical to successful DNA repair. We show that ataxia telangiectasia mutated (ATM) integrates the DNA damage response with DNA metabolism by regulating the salvage of deoxyribonucleosides. Specifically, ATM phosphorylates and activates deoxycytidine kinase (dCK) at serine 74 in response to ionizing radiation (IR). Activation of dCK shifts its substrate specificity toward deoxycytidine, increases intracellular dCTP pools post IR, and enhances the rate of DNA repair. Mutation of a single serine 74 residue has profound effects on murine T and B lymphocyte development, suggesting that post-translational regulation of dCK may be important in maintaining genomic stability during hematopoiesis. Using [18F]-FAC, a dCK-specific positron emission tomography (PET) probe, we visualized and quantified dCK activation in tumor xenografts after IR, indicating that dCK activation could serve as a biomarker for ATM function and DNA damage response in vivo. In addition, dCK-deficient leukemia cell lines and murine embryonic fibroblasts exhibited increased sensitivity to IR, indicating that pharmacologic inhibition of dCK may be an effective radiosensitization strategy.
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