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: 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.

0 Followers
 · 
102 Views
  • Source
    [Show abstract] [Hide abstract]
    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; DOI:10.1084/jem.20121061 · 13.91 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    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

Preview

Download
2 Downloads
Available from