Orchestrating B cell lymphopoiesis through interplay of IL-7 receptor and pre-B cell receptor signalling

Clark, Marcus R.; Mandal, Malay; Ochiai, Kyoko; Singh, Harinder

doi:10.1038/nri3570

Cited by 276 publications

(390 citation statements)

References 157 publications

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“…Deletion of the Btk gene was previously shown to be sufficient to cause increased IL-7 responsiveness in BM pre-B cells (20). BTK is a key component of the pre-BCR signaling pathway that functions to block IL-7R signaling in developing B cells (38). We note that the 660BM cells used in our study resemble pro-B cells rather than pre-B cells based on their lack of expression of surface IgM or Igk.…”

Section: Discussionmentioning

confidence: 93%

PU.1 Opposes IL-7–Dependent Proliferation of Developing B Cells with Involvement of the Direct Target Gene Bruton Tyrosine Kinase

Christie

Turkistany

et al. 2015

The Journal of Immunology

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Deletion of genes encoding the E26 transformation-specific transcription factors PU.1 and Spi-B in B cells (CD19-CreΔPB mice) leads to impaired B cell development, followed by B cell acute lymphoblastic leukemia at 100% incidence and with a median survival of 21 wk. However, little is known about the target genes that explain leukemogenesis in these mice. In this study we found that immature B cells were altered in frequency in the bone marrow of preleukemic CD19-CreΔPB mice. Enriched pro–B cells from CD19-CreΔPB mice induced disease upon transplantation, suggesting that these were leukemia-initiating cells. Bone marrow cells from preleukemic CD19-CreΔPB mice had increased responsiveness to IL-7 and could proliferate indefinitely in response to this cytokine. Bruton tyrosine kinase (BTK), a negative regulator of IL-7 signaling, was reduced in preleukemic and leukemic CD19-CreΔPB cells compared with controls. Induction of PU.1 expression in cultured CD19-CreΔPB pro–B cell lines induced Btk expression, followed by reduced STAT5 phosphorylation and early apoptosis. PU.1 and Spi-B regulated Btk directly as shown by chromatin immunoprecipitation analysis. Ectopic expression of BTK was sufficient to induce apoptosis in cultured pro–B cells. In summary, these results suggest that PU.1 and Spi-B activate Btk to oppose IL-7 responsiveness in developing B cells.

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Section: Discussionmentioning

confidence: 93%

PU.1 Opposes IL-7–Dependent Proliferation of Developing B Cells with Involvement of the Direct Target Gene Bruton Tyrosine Kinase

Christie

Turkistany

et al. 2015

The Journal of Immunology

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“…B-cell development is regulated by several essential chemokines or cytokines, such as IL-7 [24]. The expression of IL-7 was decreased with loss of osteoblastic Wls, maybe resulting from a secondary effect with loss of Wnt signaling.…”

Section: Discussionmentioning

confidence: 99%

“…Osteoblasts also support B-cell commitment and differentiation [22][23][24]. However, the function of Wnt signaling in osteoblastsupported B-cell development remains controversial.…”

Section: Introductionmentioning

confidence: 99%

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Ablation of Wntless in endosteal niches impairs lymphopoiesis rather than HSCs maintenance

et al. 2015

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Osteoblasts and perivascular stromal cells constitute essential niches for HSC selfrenewal and maintenance in the bone marrow. Wnt signaling is important to maintain HSC integrity. However, the paracrine role of Wnt proteins in osteoblasts-supported HSC maintenance and differentiation remains unclear. Here, we investigated hematopoiesis in mice with Wntless (Wls) deficiency in osteoblasts or Nestin-positive mesenchymal progenitor cells, which presumptively block Wnt secretion in osteoblasts. We detected defective B-cell lymphopoiesis and abnormal T-cell infiltration in the bone marrow of Wls mutant mice. Notably, no impact on HSC frequency and repopulation in the bone marrow was observed with the loss of osteoblastic Wls. Our findings revealed a supportive role of Wnts in osteoblasts-regulated B-cell lymphopoiesis. They also suggest a preferential niche role of osteoblastic Wnts for lymphoid cells rather than HSCs, providing new clues for the molecular nature of distinct niches occupied by different hematopoietic cells.Keywords: B cell r HSC maintenance r Osteoblast r T-cell infiltration r Wntless Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionHSCs that periodically generate all hematopoietic lineages are mostly stored in vascular or endosteal niches in the bone marrow [1]. Vascular niches consist of sinusoidal endothelium cells [2][3][4] whereas endosteal niches are mainly composed of osteoblasts [5,6]. These niche cells are important to regulate HSCs self-renewal and maintenance. Recent evidence also reveals that perivascular Nestin + mesenchymal progenitor cells form a supportive niche for HSCs [3,7,8]. In addition, studies from Dr. Morrison suggest that HSCs mainly reside in the perivascular niches whereas the early lymphoid progenitor cells prefer to locate at endosteal niches [9,10].Correspondence: Dr. Xizhi Guo e-mail: xzguo2005@sjtu.edu.cn; zjyao@sjtu.edu.cnCompelling evidence reveals that Wnt signaling is an important regulator for HSCs integrity and function. Wnt proteins, which consist of 19 members in mammals, could be transduced through canonical or noncanonical signaling pathways [11]. β-Catenin is the key and obligatory mediator of canonical Wnt signaling. Stabilized β-catenin expression expands the pool of HSCs and leads to deficiency in HSCs repopulation capacity [12,13]. Conversely, deletion of β-catenin or Wnt3a leads to defective HSCs long-term maintenance [14,15]. Nevertheless, several lines of evidence also indicate that β-catenin is dispensable for HSCs maintenance [16,17]. On the other hand, inhibition of environmental canonical Wnt signaling in osteoblasts impairs HSCs self-renewal and quiescence [18]. Collectively, canonical Wnt signaling is revealed to * These authors contributed equally to this work. regulate HSCs self-renewal in a dosage-dependent manner [19]. In addition, noncanonical Wnt signaling is also reported to sustain HSCs maintenance and aging [20,21]. Osteoblasts also support B-cell commitment an...

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“…21 Although primary pre-B cells stimulated in vitro by IL7 express both Cyclin D3 and Cyclin D2 (Fig. 1C), Cyclin D3 has unique function in driving proliferation of these immature B cells.…”

Section: Resultsmentioning

confidence: 99%

Lymphocyte lineage-specific and developmental stage specific mechanisms suppress cyclin D3 expression in response to DNA double strand breaks

et al. 2016

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Mammalian cells are thought to protect themselves and their host organisms from DNA double strand breaks (DSBs) through universal mechanisms that restrain cellular proliferation until DNA is repaired. The Cyclin D3 protein drives G1-to-S cell cycle progression and is required for proliferation of immature T and B cells and of mature B cells during a T cell-dependent immune response. We demonstrate that mouse thymocytes and pre-B cells, but not mature B cells, repress Cyclin D3 protein levels in response to DSBs. This response requires the ATM protein kinase that is activated by DSBs. Cyclin D3 protein loss in thymocytes coincides with decreased association of Cyclin D3 mRNA with the HuR RNA binding protein that ATM regulates. HuR inactivation reduces basal Cyclin D3 protein levels without affecting Cyclin D3 mRNA levels, indicating that thymocytes repress Cyclin D3 expression via ATM-dependent inhibition of Cyclin D3 mRNA translation. In contrast, ATM-dependent transcriptional repression of the Cyclin D3 gene represses Cyclin D3 protein levels in pre-B cells. Retrovirus-driven Cyclin D3 expression is resistant to transcriptional repression by DSBs; this prevents pre-B cells from suppressing Cyclin D3 protein levels and from inhibiting DNA synthesis to the normal extent following DSBs. Our data indicate that immature B and T cells use lymphocyte lineage-and developmental stage-specific mechanisms to inhibit Cyclin D3 protein levels and thereby help prevent cellular proliferation in response to DSBs. We discuss the relevance of these cellular context-dependent DSB response mechanisms in restraining proliferation, maintaining genomic integrity, and suppressing malignant transformation of lymphocytes.

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Orchestrating B cell lymphopoiesis through interplay of IL-7 receptor and pre-B cell receptor signalling

Cited by 276 publications

References 157 publications

PU.1 Opposes IL-7–Dependent Proliferation of Developing B Cells with Involvement of the Direct Target Gene Bruton Tyrosine Kinase

PU.1 Opposes IL-7–Dependent Proliferation of Developing B Cells with Involvement of the Direct Target Gene Bruton Tyrosine Kinase

Ablation of Wntless in endosteal niches impairs lymphopoiesis rather than HSCs maintenance

Lymphocyte lineage-specific and developmental stage specific mechanisms suppress cyclin D3 expression in response to DNA double strand breaks

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