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Previous Article | Table of Contents | Next Article Blood, Vol. 96 No. 1 (July 1), 2000: pp. 9-23 REVIEW ARTICLE Fates of human B-cell precursorsFrom the Department of Laboratory Medicine and Pathology, University of Minnesota Cancer Center, and Center for Immunology, University of Minnesota, Minneapolis.
Development of mammalian B-lineage cells is characterized by progression through a series of checkpoints defined primarily by rearrangement and expression of immunoglobulin genes. Progression through these checkpoints is also influenced by stromal cells in the microenvironment of the primary tissues wherein B-cell development occurs, ie, fetal liver and bone marrow and adult bone marrow. This review focuses on the developmental biology of human bone marrow B-lineage cells, including perturbations that contribute to the origin and evolution of B-lineage acute lymphoblastic leukemia and primary immunodeficiency diseases characterized by agammaglobulinemia. Recently described in vitro and in vivo models that support development and expansion of human B-lineage cells through multiple checkpoints provide new tools for identifying the bone marrow stromal cell-derived molecules necessary for survival and proliferation. Mutations in genes encoding subunits of the pre-B cell receptor and molecules involved in pre-B cell receptor signaling culminate in X-linked and non-X-linked agammaglobulinemia. A cardinal feature of these immunodeficiencies is an apparent apoptotic sensitivity of B-lineage cells at the pro-B to pre-B transition. On the other end of the spectrum is the apoptotic resistance that accompanies the development of B-lineage acute lymphoblastic leukemia, potentially a reflection of genetic abnormalities that subvert normal apoptotic programs. The triad of laboratory models that mimic the bone marrow microenvironment, immunodeficiency diseases with specific defects in B-cell development, and B-lineage acute lymphoblastic leukemia can now be integrated to deepen our understanding of human B-cell development. (Blood. 2000;96:9-23)
Development of mature blood cells from lymphohematopoietic progenitors is a complex process governed by sequential changes in gene expression and external cues emanating from lymphohematopoietic microenvironments, such as fetal liver and bone marrow (BM). The last decade has witnessed dramatic progress in elucidating the molecular mechanisms that govern blood cell development. Mice with alterations in gene content (transgenics, knockouts, knockins) have been extraordinarily useful in elucidating the role of transcription factors, cytokines, and cytokine receptors in blood cell development. This review focuses on the developmental biology of human BM B-lineage cells and on perturbations in development that can contribute to the progression of B-lineage acute lymphoblastic leukemia (ALL) and immunodeficiency diseases characterized by agammaglobulinemia. My objective is to provide an update on key issues in human B-cell development and, where appropriate, compare and contrast B-cell development in mouse and human. The discussion of B-lineage ALL and immunodeficiency diseases will consider the developmental biology of these diseases as they constitute a deviation from normal programs. The terminology used in this review is largely consistent with the terminology used by other laboratories studying human B-cell development. Pro-B cells are those B-lineage cells that express cell-surface CD19 but do not express cytoplasmic or cell-surface µ heavy chains (HCs). Pre-B cells express cell-surface CD19 and cytoplasmic µHCs, and variably express cell-surface µHCs associated with surrogate light chains (LCs)ie, the pre-B cell receptor (pre-BCR). Immature B cells express cell-surface CD19 and cell-surface µHCs associated with or LCsie, the B-cell receptor (BCR). B-cell precursors include all B-lineage cells prior to immature B cells expressing the BCR.
Human B-lineage cells are present in multiple tissue sites in early fetal development. However, from midgestation through the eighth decade of life, the BM is the exclusive site of B lymphopoiesis. Pre-B cells are present in 7- to 8-week gestational age fetal liver1 and 10-week gestational age fetal omentum.2 A thorough analysis of 18- to 20-week fetal tissues revealed that B-cell development is multifocal; CD19+/surface µHC B-cell precursors and CD19+/surface µHC+ immature B cells are present in BM, liver, lung, kidneys, and spleen.3 The frequency of B-cell precursors as a percentage of the total lymphoid cell pool is much higher in fetal BM compared with adult BM.3,4 Adult BM also differs from fetal BM by the presence of recirculating CD19+/surface µ, HC+ mature B cells in the former.3 Similar levels of recombinase-activating gene (RAG)-1, RAG-2, and terminal deoxynucleotidyl transferase (TdT) are detectable by reverse transcriptase-polymerase chain reaction (RT-PCR) in pro-B cells from 18-week fetal BM and 62-year adult BM, underscoring the functional integrity of BM B-cell development throughout life.3 It is noteworthy that recent studies of T-cell development indicate that T-cell receptor (TCR) gene rearrangements actively occur in thymocytes from individuals in their sixth decade of life.5 Thus, ongoing development of B and T lymphocytes throughout life complements the existence of memory B and T lymphocytes in maintaining a functional immune system.
Analysis of gene expression in developing lymphoid cells can be accomplished by multiparameter flow cytometry, immunohistochemistry/fluorescence microscopy, and RT-PCR. Immunologic phenotyping of B-lineage ALL using monoclonal antibodies (mAbs) and flow cytometry has been conducted in many laboratories, and it is not my intent to summarize the many published reports. The reader is referred elsewhere for an in-depth review.6
Mammalian B-lineage cells must traverse several critical checkpoints on the road to becoming functional antigen-specific B cells. The cell surface molecular complex appearing at a critical initial checkpoint is the pre-BCR. The pre-BCR is a complex of proteins consisting of µHC, LC, and the Ig/Ig signal transducing heterodimer.31 The mammalian LC consists of 2 proteins generally referred to as VpreB and 5. The genes encoding these 2 proteins were originally discovered in the mouse (Melchers et al32 and references therein) and their organization differs between mouse and human (Minegishi et al33 and references therein) VpreB and 5 proteins are noncovalently associated on the surface of B-cell precursors and together form a LC-like structure. In turn, 5 is covalently coupled to the CH1 domain of µHC via a carboxy-terminal cysteine. Readers are referred to an earlier review for details on the original identification and characterization of the VpreB and 5 genes and their encoded proteins.32
An unresolved issue in studies of human B-cell development is the identity of the molecule(s) essential for the growth of normal B-cell precursors. Much has been written of IL-7, and some historical perspective is warranted. Following the initial cloning and characterization of IL-7 from murine BM stromal cells more than 10 years ago,59 IL-7 was shown to be crucial for the proliferation and development of murine B-cell precursors. IL-7 has been cast as a survival, proliferation, or differentiation factor depending upon the experimental system being employed.60,61 Mechanistic insight has been gleaned from studying the effect of single amino acid substitutions on IL-7R chain function. Corcoran and colleagues showed that a Y-to-F mutation at amino acid residue 449 abrogated the capacity of B-cell precursors to undergo IL-7-induced proliferation through a PI-3 kinase-dependent pathway.62 Interestingly, functional studies of the IL-7R chain harboring this mutation uncovered a novel signaling pathway (PI-3 kinase independent?) that triggered IgH rearrangements and subsequent B-cell differentiation.62 Recent studies from the same group indicated that IL-7R signaling can alter recombinase accessibility of 5' VH genes.63 The criticality of IL-7 for normal murine B-cell development has been elucidated in gene-targeted mice. Targeted disruptions in the genes encoding IL-7,64 the IL-7R chain,65 the c subunit of the receptors for IL-2, 4, 7, 9, and 15,66,67 and the Jak3 tyrosine kinase68,69 all lead to severe impairment in B-cell development. Thymocyte and T-cell development are also impaired, reflecting the multiple actions these 5 cytokines exert on lymphopoiesis. IL-7 is, however, not the only cytokine implicated in the regulation of murine B-cell development. Kincade and colleagues have suggested that at least 16 distinct stromal cell products can exert positive effects on murine B-cell development.61 One recent addition to the list is thymic stromal lymphopoietin (TSLP). TSLP was originally isolated from a murine thymic stromal cell line.70 TSLP reportedly has the capability to replace IL-7 in supporting murine B-cell development in vitro71 and promote the development of surface IgM+ immature B cells from surface IgM precursors.72 Interestingly, the TSLP receptor complex consists of the IL-7R chain and a second subunit distinct from the c. Furthermore, TSLP induced the activation of STAT5 but not any of the known Jak kinases.72 Whether IL-7 and TSLP work in a hierarchical or cooperative manner in regulating murine B-cell development is unknown. Human TSLP has been cloned (S. Lyman, PhD, Immunex, written communication, May 1999), but there are no published reports on its bioactivity on human B-cell precursors.
Establishment and characterization of in vitro culture systems that at least partially mimic the in vivo BM microenvironment have been extremely important for advancing our understanding of human B-cell development. Progress in this area has been facilitated by the use of BM stromal cells as a supportive microenvironment. Adherence of B-cell precursors to BM stromal cells is essential for normal murine and human B-cell development (reviewed in Kincade et al,61 Jarvis et al,105 and Ryan et al106). Binding of very late antigen-4 (VLA-4) (CD49d/CD29) expressed on human B-cell precursors to VCAM-1 on human BM stromal cells is the primary molecular interaction that facilitates adhesion of these 2 cell types.107-109 Cytokines can regulate levels of BM stromal cell surface VCAM-1, thereby influencing the capacity of these cells to support B-cell precursor adhesion.108 There is substantial evidence that cross-linking VLA-4 with VCAM-1 or the CS-1 domain of fibronectin can trigger a protein tyrosine kinase cascade in B-lineage cells. However, there is no evidence that VLA-4 triggers a reciprocal activation of VCAM-1 culminating in a signal transduced in BM stromal cells. Lymphoid cell contact with human BM stromal cells can transduce signals leading to protein tyrosine kinase activation110 and tyrosine phosphorylation of focal adhesion kinase, paxillin, and ERK2.111 This signaling pathway is independent of VCAM-1.110 To what degree these bi-directional (B-cell precursor BM stromal cell) signaling events might influence B-cell developmental fates in vivo is unknown.
Dramatic progress has recently been made in identifying the genetic defects in many congenital human immunodeficiency diseases.131 These diseases are largely classified on the basis of which cellular component or function of the immune response is defective.132 By the grace of good hindsight, it is not surprising that immunodeficiency diseases that primarily affect B-cell development or B-cell function involve genes encoding protein components of the pre-BCR, BCR, or signaling pathways activated following cross-linking these receptors.133 The degree to which B-cell development or function is altered in these patients shows many similarities and some differences compared with the phenotype observed in gene-targeted mice.
XLA is the prototype immunodeficiency disease that specifically affects the B-lineage.131-133 The Bruton's tyrosine kinase (BTK) gene encodes a cytosolic 659-amino acid protein that is mutated in the vast majority of boys diagnosed with XLA.134,135 BTK mutations are found in 80% to 90% of patients following a presumptive diagnosis of XLA based on early-onset hypogammaglobulinemia and few or no detectable peripheral blood B cells.136 More than 300 mutations have been identified in the BTK gene,137 and mutations have been mapped to all 6 of the functional domains.138 The majority of XLA patients have profound hypogammaglobulinemia afflicting all immunoglobulin classes and fewer than 1% of normal numbers of peripheral blood B cells. A single study of 8 patients indicated that maturation arrest occurred at the pro-B/pre-B interface, ie, between CD19+/TdT+/cytoplasmic µHC and CD19+/TdT/cytoplasmic µHC+ populations.139
As discussed above, 10% to 20% of B-lineage immunodeficiency patients do not harbor BTK mutations. Mary Ellen Conley and her colleagues have systematically screened BM DNA samples from patients lacking BTK mutations in an effort to identify other mutated genes that could underlie these immunodeficiency diseases. By this approach, they have identified patients with mutations in the µHC,150 the 5/14.1 component of the LC,33 and Ig.151 Seven patients from 3 families harbored mutations that disrupted the µHC.150 These included 75-kb to 100-kb homozygous deletions of the D and J regions plus the µ constant region, and a homozygous base-pair substitution that removed an alternate splice site used to generate the membrane form of the µHC. Analysis of peripheral blood from 4 of 7 patients revealed no detectable B cells, and analysis of the BM from 1 of the 4 evaluable patients indicated maturation arrest at the pro-B to pre-B interface.150 In a second report, a 5-year-old boy with severe hypogammaglobulinemia was found to have fewer than 1% of the normal number of peripheral blood B cells.33 A detailed analysis of the mutated 5 alleles and their encoded proteins suggested that the mutated 5 protein underwent improper folding and was subsequently degraded.33 Analysis of this patient's BM suggested a block at the pro-B to pre-B transition. In the most recent report, a 2-year-old girl with agammaglobulinemia was found to have a deletion of exon 3 in the gene encoding Ig.151 This exon encodes the transmembrane domain of Ig leading to the prediction that the Ig transcript made in this patient would encode a truncated protein incapable of assembling with the pre-BCR. Analysis of this patient further revealed the complete absence of peripheral blood B cells and a block at the pro-B to pre-B transition. A non-XLA patient with a block at the pro-B cell stage and a decrease in Ig, Ig, and VH-Cu transcripts may represent yet another distinct mutation in genes essential for B-cell development.152 It is remarkable that mutations in BTK and genes encoding components of the pre-BCR can lead to a relatively similar block in B-cell development at the pro-B to pre-B transition. Figure 4 suggests why this may occur. Expression of the pre-BCR requires assembly of the µHC, LC, and Ig/Ig subunits. Any mutation that leads to an absence of one subunit will block full assembly of the pre-BCR. The physical absence of an intact pre-BCR will result in a failure of the pre-BI compartment (Figure 2) to expand. Independently of how the pre-BCR signals, the presence of the Ig/Ig heterodimer predicts that pre-BCR and BCR signaling pathways will be highly conserved.31,138 Thus, in XLA patients, pre-BCR cross-linking would be normal at least to the point where BTK is translocated to the membrane, but BTK-dependent events leading to a sustained increase in Ca++ flux would be greatly decreased or absent (Figure 4).
In approximately 75% of pediatric patients with newly diagnosed ALL, the disease is classified as B-lineage in origin on the basis of immunoglobulin gene rearrangements and expression of cell surface markers.153-155 The karyotypic and molecular genetic abnormalities in B-lineage ALL have been extensively characterized,153-155 and chromosomal translocations giving rise to distinct fusion genes including TEL-AML1, MLL-AF4 (or MLL rearrangements with other genes), and E2A-PBX are present in more than 30% of newly diagnosed pediatric B-lineage ALL.153 However, the totality of molecular genetic abnormalities in B-lineage ALL is much greater than these landmark translocations. Despite this impressive progress, there is still a deficiency in our understanding of how these many genetic abnormalities ultimately subvert normal B-cell precursor developmental programs. Related questions are how these genetic abnormalities tip the survival scale to apoptotic resistance and whether external cues (ie, cytokines) play any role in regulating the survival/growth of B-lineage ALL in vivo.
The general blueprint for mammalian B-cell development has been determined, and the investigative fine-tuning has begun. A number of questions regarding human B-cell development remain unanswered. For example, how does a B-lineage cell develop from a multilineage progenitor (eg, a CLP in Figure 1), and how is B-lineage commitment defined in molecular terms? Transcription factors are obviously the key. One of the great accomplishments in hematology during the nineties was the isolation and characterization of transcription factors that regulate the development of murine lymphohematopoietic lineages (for recent reviews, see Glimcher et al211 and Engel et al212). A stunning recent discovery directly implicated the paired box transcription factor PAX5 in murine B-lineage commitment.213,214 The major message from these 2 studies is that PAX5-deficient murine pro-B cells (ie, B-lineage cells that have undergone DJH but not VDJH rearrangements) harbor the capacity to differentiate into a constellation of other lineagesincluding macrophages, osteoclasts, dendritic cells, granulocytes, NK cells, and thymocytes.213,214 This surprising result was used to propose that PAX5 plays an essential role in fostering B-lineage commitment by suppressing the expression of genes that (directly or indirectly) promote development of non-B lineage cells. It is reasonable to assume that human B-lineage commitment and development are governed by similar transcription factors, but is there experimental evidence? Answers may be forthcoming. Jaleco and colleagues have very recently described a strategy that represents the first success in elucidating the role of transcription factors in human B-cell development. They constructed a retroviral vector encoding green fluorescent protein (GFP) and the dominant negative helix loop helix protein Id3.215 Human fetal liver HSCs were then infected with this vector and plated on murine or human stromal cells, and GFP expression was used to trace the effect of overexpression of Id3 on B-cell development. The results indicated that Id3 overexpression blocked B-cell development at a stage prior to expression of the IL-7 receptor.
Mary Ellen Conley (St. Jude Children's Research Hospital) and Les Silberstein (Harvard Medical School) kindly provided preprints of their work. I thank Ted Bertrand for helpful comments on the manuscript and Sandi Sherman for word-processing support.
Submitted November 30, 1999; accepted February 2, 2000. Supported by grants R01 CA31685 and R01 CA76055 from the National Cancer Institute, National Institutes of Health, Bethesda, MD. Reprints: Tucker W. LeBien, University of Minnesota Cancer Center, 420 Delaware St SE, Box 806 Mayo, University of Minnesota, Minneapolis, MN 55455; e-mail: lebie001{at}tc.umn.edu. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
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N. Shah, R. J. Asch, A. S. Lysholm, and T. W. LeBien Enhancement of stress-induced apoptosis in B-lineage cells by caspase-9 inhibitor Blood, November 1, 2004; 104(9): 2873 - 2878. [Abstract] [Full Text] [PDF] |
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A. M. Glodek, M. Honczarenko, Y. Le, J. J. Campbell, and L. E. Silberstein Sustained Activation of Cell Adhesion Is a Differentially Regulated Process in B Lymphopoiesis J. Exp. Med., February 17, 2003; 197(4): 461 - 473. [Abstract] [Full Text] [PDF] |
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L. J. N. Cooper, M. S. Topp, L. M. Serrano, S. Gonzalez, W.-C. Chang, A. Naranjo, C. Wright, L. Popplewell, A. Raubitschek, S. J. Forman, et al. T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B-lineage leukemia effect Blood, February 15, 2003; 101(4): 1637 - 1644. [Abstract] [Full Text] [PDF] |
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Y.-H. Wang, Z. Zhang, P. D. Burrows, H. Kubagawa, S. L. Bridges Jr, H. W. Findley, and M. D. Cooper V(D)J recombinatorial repertoire diversification during intraclonal pro-B to B-cell differentiation Blood, February 1, 2003; 101(3): 1030 - 1037. [Abstract] [Full Text] [PDF] |
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Y. Hashimoto, E. Montecino-Rodriguez, H. Leathers, R. P. Stephan, and K. Dorshkind B-cell development in the thymus is limited by inhibitory signals from the thymic microenvironment Blood, November 15, 2002; 100(10): 3504 - 3511. [Abstract] [Full Text] [PDF] |
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K. S. Smith, J. W. Rhee, and M. L. Cleary Transformation of Bone Marrow B-Cell Progenitors by E2A-HLF Requires Coexpression of BCL-2 Mol. Cell. Biol., November 1, 2002; 22(21): 7678 - 7687. [Abstract] [Full Text] [PDF] |
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M. Honczarenko, Y. Le, A. M. Glodek, M. Majka, J. J. Campbell, M. Z. Ratajczak, and L. E. Silberstein CCR5-binding chemokines modulate CXCL12 (SDF-1)-induced responses of progenitor B cells in human bone marrow through heterologous desensitization of the CXCR4 chemokine receptor Blood, September 18, 2002; 100(7): 2321 - 2329. [Abstract] [Full Text] [PDF] |
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J. M. Kim, J. Fang, S. Rheingold, R. Aplenc, R. Wasserman, and S. A. Grupp Cytoplasmic {micro} Heavy Chain Confers Sensitivity to Dexamethasone-induced Apoptosis in Early B-lineage Acute Lymphoblastic Leukemia Cancer Res., August 1, 2002; 62(15): 4212 - 4216. [Abstract] [Full Text] [PDF] |
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M. Muschen, S. Lee, G. Zhou, N. Feldhahn, V. S. Barath, J. Chen, C. Moers, M. Kronke, J. D. Rowley, and S. M. Wang Molecular portraits of B cell lineage commitment PNAS, July 23, 2002; 99(15): 10014 - 10019. [Abstract] [Full Text] [PDF] |
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I. Mikkola, B. Heavey, M. Horcher, and M. Busslinger Reversion of B Cell Commitment upon Loss of Pax5 Expression Science, July 5, 2002; 297(5578): 110 - 113. [Abstract] [Full Text] [PDF] |
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M. Hotfilder, S. Rottgers, A. Rosemann, H. Jurgens, J. Harbott, and J. Vormoor Immature CD34+CD19- progenitor/stem cells in TEL/AML1-positive acute lymphoblastic leukemia are genetically and functionally normal Blood, June 28, 2002; 100(2): 640 - 646. [Abstract] [Full Text] [PDF] |
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E. R. Panzer-Grumayer, K. Fasching, S. Panzer, K. Hettinger, K. Schmitt, S. Stockler-Ipsiroglu, and O. A. Haas Nondisjunction of chromosomes leading to hyperdiploid childhood B-cell precursor acute lymphoblastic leukemia is an early event during leukemogenesis Blood, June 17, 2002; 100(1): 347 - 349. [Abstract] [Full Text] [PDF] |
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R. Gisler and M. Sigvardsson The Human V-PreB Promoter Is a Target for Coordinated Activation by Early B Cell Factor and E47 J. Immunol., May 15, 2002; 168(10): 5130 - 5138. [Abstract] [Full Text] [PDF] |
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Y.-H. Wang, R. P. Stephan, A. Scheffold, D. Kunkel, H. Karasuyama, A. Radbruch, and M. D. Cooper Differential surrogate light chain expression governs B-cell differentiation Blood, April 1, 2002; 99(7): 2459 - 2467. [Abstract] [Full Text] [PDF] |
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F. E. Bertrand, C. Vogtenhuber, N. Shah, and T. W. LeBien Pro-B-cell to pre-B-cell development in B-lineage acute lymphoblastic leukemia expressing the MLL/AF4 fusion protein Blood, December 1, 2001; 98(12): 3398 - 3405. [Abstract] [Full Text] [PDF] |
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J. Storek, D. Wells, M. A. Dawson, B. Storer, and D. G. Maloney Factors influencing B lymphopoiesis after allogeneic hematopoietic cell transplantation Blood, July 15, 2001; 98(2): 489 - 491. [Abstract] [Full Text] [PDF] |
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N. Shah, L. Oseth, H. Tran, B. Hirsch, and T. W. LeBien Clonal Variation in the B-Lineage Acute Lymphoblastic Leukemia Response to Multiple Cytokines and Bone Marrow Stromal Cells Cancer Res., July 1, 2001; 61(13): 5268 - 5274. [Abstract] [Full Text] [PDF] |
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A. Bennaceur-Griscelli, C. Pondarre, V. Schiavon, W. Vainchenker, and L. Coulombel Stromal cells retard the differentiation of CD34+CD38low/neg human primitive progenitors exposed to cytokines independent of their mitotic history Blood, January 15, 2001; 97(2): 435 - 441. [Abstract] [Full Text] [PDF] |
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S Puch, S Armeanu, C Kibler, K. Johnson, C. Muller, M. Wheelock, and G Klein N-cadherin is developmentally regulated and functionally involved in early hematopoietic cell differentiation J. Cell Sci., January 4, 2001; 114(8): 1567 - 1577. [Abstract] [PDF] |
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