Flt3 ligand supports the differentiation of early B cell progenitors in the presence of interleukin‐11 and interleukin‐7

Ray, Robert J.; Paige, Christopher J.; Furlonger, Caren; Lyman, Stewart D.; Rottapel, Robert

doi:10.1002/eji.1830260715

Cited by 97 publications

(48 citation statements)

References 46 publications

(18 reference statements)

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“…We have previously described a culture system that allows for the maturation of B cell progenitors from lineage uncommitted cells through to the IgM-secreting mature B cell stage (12)(13)(14). Consequently, this culture system supports any required signaling by the preBCR or other receptors necessary to mediate this maturation.…”

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confidence: 99%

Heparan Sulfate and Heparin Enhance ERK Phosphorylation and Mediate preBCR-Dependent Events during B Lymphopoiesis

Milne

Corfe

Paige

2008

The Journal of Immunology

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As B lineage cells develop, they interact with cells, proteins, and extracellular matrix components of the surrounding microenvironment. In vitro, one critical checkpoint for developing cells occurs as they lose responsiveness to IL-7. These cells require contact with either stromal cells or other B lineage cells to mature. Our results demonstrate that heparan sulfate and heparin are able to promote this transition when added exogenously to the culture system or when heparan sulfate-bearing cell lines are cocultured with primary B cell progenitors. Addition of heparan sulfate or heparin to LPS-stimulated cultures of primary B cell progenitors resulted in more IgM secreted compared with untreated cultures. Heparan sulfate has been reported to be a ligand for the pre-B cell receptor (preBCR). Extending this observation, we found that treatment of preBCR+ cells with heparan sulfate before anti-μ stimulation leads to increased phosphorylation of ERK1/2. Consequently, preBCR+ cells proliferate more in the presence of IL-7 and heparan sulfate, whereas preBCR− cells are unaffected, suggesting that in these experiments, heparan sulfate is not directly affecting IL-7 activity. Heparin treatment of cultures induces many of the same biological effects as treatment with heparan sulfate, including elevated pERK levels in preBCR+ cells. However, heparin reduces the proliferation of cells expressing only the preBCR (opposed to both the preBCR and BCR) possibly due to internalization of the preBCR. Heparan sulfates are present on stromal cells and B lineage cells present in hemopoietic tissues and may provide stimulation to preB cells testing the signaling capacity of the preBCR.

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Heparan Sulfate and Heparin Enhance ERK Phosphorylation and Mediate preBCR-Dependent Events during B Lymphopoiesis

Milne

Corfe

Paige

2008

The Journal of Immunology

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“…Similarly, Flt3L-deficient mice have significantly reduced numbers of CLPs, B-cell progenitors, DCs, and natural killer (NK) cells (McKenna et al 2000). Flt3L expressed by bone marrow stroma (Lisovsky et al 1996), is a weak growth stimulator of Flt3 + CLPs in vitro and synergizes with stem cell factor (SCF) and IL-7 to promote the proliferation of lymphocytes and, most potently, DCs (Ray et al 1996;Saunders et al 1996;Veiby et al 1996). The ability of Flt3 to promote the expression of the IL-7 receptor on CLPs provides a mechanism by which this synergy occurs in early lymphopoiesis (Borge et al 1999).…”

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Repression of Flt3 by Pax5 is crucial for B-cell lineage commitment

Holmes¹,

Carotta²,

Corcoran³

et al. 2006

Genes Dev.

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Early B-lymphopoiesis requires the growth-factor receptors, IL-7R and Flt3, and the activity of a number of transcription factors. One factor, Pax5, is required for commitment to the B-cell lineage, although the molecular mechanism by which this occurs is unknown. We demonstrate here that an important function of Pax5 is to repress Flt3 transcription in B-cell progenitors, as Pax5-deficient pro-B cells express abundant Flt3 that is rapidly silenced upon the reintroduction of Pax5, whereas enforced expression of Flt3 in wild-type progenitors significantly impairs B-cell development. These findings demonstrate that the repression of Flt3 by Pax5 is essential for normal B-lymphopoiesis. Hematopoietic stem cells (HSCs) have the dual capacity to self-renew and to give rise to cells of all the blood lineages. Although the identity and diversity of the intermediaries is still not completely understood, it is clear that an early differentiation step from the HSC gives rise to multipotent progenitors that have reduced capacity to self-renew. These progenitors up-regulate the tyrosine kinase receptor Flt3 (also termed flk2 and CD135) (Adolfsson et al. 2001) and efficiently reconstitute the lympho-myeloid but not the erythro-megakaryocytic lineages (Adolfsson et al. 2005). Flt3 is later expressed on a subset of common myeloid progenitors, with dendritic cell (DC) potential (D'Amico and Wu 2003), and common lymphoid progenitors (CLPs) (Sitnicka et al. 2002).Flt3 −/− mice have a severe deficiency in B-cell progenitors, and the mutant HSCs are impaired in their ability to reconstitute lymphoid and myeloid cells in recipient mice (Mackarehtschian et al. 1995). Similarly, Flt3L-deficient mice have significantly reduced numbers of CLPs, B-cell progenitors, DCs, and natural killer (NK) cells (McKenna et al. 2000). Flt3L expressed by bone marrow stroma (Lisovsky et al. 1996), is a weak growth stimulator of Flt3 + CLPs in vitro and synergizes with stem cell factor (SCF) and IL-7 to promote the proliferation of lymphocytes and, most potently, DCs (Ray et al. 1996;Saunders et al. 1996;Veiby et al. 1996). The ability of Flt3 to promote the expression of the IL-7 receptor on CLPs provides a mechanism by which this synergy occurs in early lymphopoiesis (Borge et al. 1999).B-cell specification is controlled by the coordinate activity of a number of transcription factors, including E2A and EBF, which regulate rearrangement of the IgH locus and pre-B-cell receptor expression (for review, see Busslinger 2004;Singh et al. 2005). These factors also induce Pax5, which is essential for the restriction of lymphoid progenitors to the B-cell fate ). In the absence of Pax5, B lymphopoiesis in the bone marrow is blocked at the early pro-B (or pre-BI)-cell stage (Urbanek et al. 1994;Nutt et al. 1997). Analysis of Pax5 −/− pro-B cells has demonstrated that Pax5 plays a dual role in B-cell commitment, activating lineage-specific genes such as CD19 and mb-1 while repressing lineage inappropriate genes such as M-CSR, and Notch1 (Nutt et al. 1998;Souabni ...

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“…Soluble forms activate the corresponding FLT3 receptor [3] Although its messenger RNA is detected in most hematopoietic and nonhematopoietic tissues, protein expression is restricted to T lymphocytes and BM stromal cells composing the hematopoietic microenvironment [15][16][17]. Generally, FL acts in combination with other cytokines, resulting in strongly synergistic effects; isolated addition of FL to stem/progenitor cell cultures has no significant effect on proliferation of myeloid and lymphoid progenitors [18][19][20][21].…”

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confidence: 99%