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: 19.75). 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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    • "To examine the functional consequences of dCTP deficiency and RS, we analyzed the cell cycle profiles of highly proliferative subpopulations that we found to be selectively depleted (e.g., T and B cell precursors) or overrepresented (erythroblast precursors) among dCK / hematopoietic progenitor populations (Fig. S1). These highly proliferative subpopulations included DN3b T cell precursors (CD4  , CD8  , CD44  , CD25 med-lo , and CD27 hi thymocytes; Taghon et al., 2006), Hardy fraction B-C B cell progenitors (IgM  , B220 + , CD43 hi , and CD19 hi ; Hardy et al., 2007), and nucleated erythroblast cells (EryA; Ter119 + , CD71 + , and FSC hi ; Liu et al., 2006). dCK / cells from all three progenitor populations showed abnormal cell cycle profiles (Fig. 1 D), with dCK / EryA cells displaying the most pronounced increase in the percentage of cells in S-phase. "
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    ABSTRACT: Nucleotide deficiency causes replication stress (RS) and DNA damage in dividing cells. How nucleotide metabolism is regulated in vivo to prevent these deleterious effects remains unknown. In this study, we investigate a functional link between nucleotide deficiency, RS, and the nucleoside salvage pathway (NSP) enzymes deoxycytidine kinase (dCK) and thymidine kinase (TK1). We show that inactivation of dCK in mice depletes deoxycytidine triphosphate (dCTP) pools and induces RS, early S-phase arrest, and DNA damage in erythroid, B lymphoid, and T lymphoid lineages. TK1(-/-) erythroid and B lymphoid lineages also experience nucleotide deficiency but, unlike their dCK(-/-) counterparts, they still sustain DNA replication. Intriguingly, dCTP pool depletion, RS, and hematopoietic defects induced by dCK inactivation are almost completely reversed in a newly generated dCK/TK1 double-knockout (DKO) mouse model. Using NSP-deficient DKO hematopoietic cells, we identify a previously unrecognized biological activity of endogenous thymidine as a strong inducer of RS in vivo through TK1-mediated dCTP pool depletion. We propose a model that explains how TK1 and dCK "tune" dCTP pools to both trigger and resolve RS in vivo. This new model may be exploited therapeutically to induce synthetic sickness/lethality in hematological malignancies, and possibly in other cancers.
    Journal of Experimental Medicine 11/2012; 209(12). DOI:10.1084/jem.20121061 · 13.91 Impact Factor
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    • "B-2 cells are present in secondary lymphoid organs and are generally considered to be mediators of adaptive immunity. They include a predominant population of follicular (FO) and a minor population of marginal zone (MZ) B cells, both of which can undergo Ig class switching and differentiate into memory cells (Martin and Kearney, 2002; Allman and Pillai, 2008; Hardy et al., 2007; Monroe and Dorshkind, 2007). "
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    ABSTRACT: Models of hematopoiesis often depict lymphocyte production as a uniform process in which a homogenous population of hematopoietic stem cells (HSCs) generates progenitors from which all types of lymphocytes are derived. However, it is increasingly evident that these schemes are too simplistic and that the lymphoid potential of HSCs and precursors arising in the embryo, fetus, neonate, and adult is remarkably distinct. We review recent findings regarding the development of B lymphocytes, and the B-1 B cell lineage in particular, as a case in point. These studies show that B-1 and B-2 B cells involved in innate and adaptive immune responses, respectively, arise in staggered waves of development from distinct progenitors. We discuss the implications of this layered model of B cell development for understanding normal and dysregulated B lymphopoiesis.
    Immunity 01/2012; 36(1):13-21. DOI:10.1016/j.immuni.2011.11.017 · 19.75 Impact Factor
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    • "Hematopoietic stem and progenitor cells (HSPC) derived from the middle-stage FL still lacked estrogen receptors even four weeks after transplantation to irradiated RAG-1-deficient mice (Igarashi et al., 2001). An increasing body of evidence has provided information on the differences between FL and adult-BM hematopoietic cells (Bowie et al., 2007; Hardy and Hayakawa, 1991; Hardy et al., 2007; Irion et al., 2010; Medina and Kincade, 1994; Montecino-Rodriguez et al., 2006; Siggs et al., 2011). Kikuchi et al. (2005) have demonstrated that regarding the IL-7 receptor expression, the conversion from FL phenotype to adult phenotype occurs in mice during the first few weeks after birth. "
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    ABSTRACT: Adult B-lymphopoiesis is suppressed by the inhibitory effects of elevated estrogens during pregnancy. At the same time, hematopoietic cells in the fetal liver are resistant to this suppression by estrogens and ensure active production of B-cells. We investigated whether this unresponsiveness to estrogens of fetal cells also applies to cells obtained from a newborn liver and projects into the adult hematopoiesis when fetal liver cells are transplanted to adult mice. Mixtures of fetal liver (E14.5), neonatal liver (P0.5) and adult bone marrow (BM) cells were co-transplanted into adult primary and secondary recipients treated with high doses of estrogen in the Ly5.1/Ly5.2 congenic mouse model. Total chimerism as a proportion of all nucleated blood cells, chimerism as a proportion of B220+ B-cells, and of other blood cell lineages as well, were determined by flow cytometry. B-lymphopoiesis derived from fetal liver (E14.5) stem cells remained resistant to estrogen after transplantation into both primary and secondary adult recipients, for up to 280 days. In contrast, B-lymphopoiesis derived from neonatal liver (P0.5) stem cells was resistant to estrogen only for approximately 50 days after the primary transplantation to the adult BM microenvironment. These results provide further evidence for a critical developmental period of B-lymphopoiesis during its fetal liver stage. In the mouse, critical developmental events that allow for the subsequent expressed sensitivity of B-lymphopoiesis for suppression by estrogens after sexual maturation appear to occur during the period of late-stage fetal liver hematopoiesis before its migration to the bone marrow.
    Developmental and comparative immunology 08/2011; 36(2):385-9. DOI:10.1016/j.dci.2011.07.009 · 3.71 Impact Factor
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