Extensive in vivo self-renewal, long-term reconstitution capacity, and hematopoietic multipotency of Pax5-deficient precursor B-cell clones

Schaniel, Christoph; Gottar, Marie; Roosnek, Eddy; Melchers, Fritz; Rolink, Antonius

doi:10.1182/blood.v99.8.2760

Cited by 54 publications

(33 citation statements)

References 36 publications

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“…Pax5 -/-pro-B cells can be cultured indefinitely on stromal co-cultures in the presence of IL-7 and have many characteristics of B cell progenitors [16]. Subsequent studies have, however, demonstrated that Pax5 -/-pro-B cells maintain a broad lympho-myeloid potential in vitro and in vivo [16][17][18][19]. When injected into mice deficient for T, B and NK cells (Rag2 -/-cc -/-), Pax5 -/-pro-B cells reconstitute the T cell compartment as well as differentiate into DC, myeloid cells and NK cells, whereas in vitro assays have efficiently generated macrophages and DC from these cells in the presence of the appropriate cytokines.…”

Section: Introductionmentioning

confidence: 99%

Transient Notch signaling induces NK cell potential in Pax5‐deficient pro‐B cells

Carotta

Brady

et al. 2006

Eur J Immunol

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Unlike early B/T cell development, NK cell lineage commitment is not well understood, with a major limitation being the lack of a robust culture system to assay NK cell progenitors. Here we have exploited the multi‐lineage potential of Pax5–/– pro‐B cells to establish an effective system to direct differentiation of progenitors into the NK cell lineage. Cultivation of Pax5–/– pro‐B cells on OP9 cells expressing the Notch ligand Delta‐Like1 (OP9‐DL1) in the presence of IL‐7 efficiently induced T and NK cell potential. For NK cells, Notch was only transiently required, as prolonged signaling decreased NK and increased T cell development. Pure NK cell populations could be obtained by the culture of these Notch signal‐experienced cells onto OP9 stroma and IL‐15. A similar transient exposure to Notch was also compatible with the differentiation of NK cells from hematopoietic progenitors, while sustained Notch signaling impaired NK cell generation. Pax5–/– pro‐B cell‐derived NK cells were cytotoxic, secreted cytokines and expressed all the expected NK cell‐specific surface markers examined except the Ly49 family, a phenotype similar to fetal NK cells. These data indicate that Notch signaling induces T/NK cell differentiation in Pax5–/– pro‐B cells that is strikingly similar to early thymopoiesis.

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Section: Introductionmentioning

confidence: 99%

Transient Notch signaling induces NK cell potential in Pax5‐deficient pro‐B cells

Carotta

Brady

et al. 2006

Eur J Immunol

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“…B-lineage commitment from common lymphoid progenitors is initiated with a transcription factor, PAX5, which presumably suppresses differentiation toward other lineages (1)(2)(3). EBF and E2A are two other B lineage-specific transcription factors that work at an early developmental stage (4,5).…”

Section: Introductionmentioning

confidence: 99%

A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans

Sawada¹,

Takihara²,

Kim³

et al. 2003

J. Clin. Invest.

148

105

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“…B-cell development in Pax5-deficient mice is arrested at the early pro-B-cell stage in the bone marrow (Nutt et al 1997), and Pax5-null pro-B cells can differentiate into multiple non-B-cell hematopoietic lineages in vitro and in vivo Rolink et al 1999;Schaniel et al 2002). Pax5 drives B-lineage commitment by transcriptionally activating B-lineage-specific gene expression networks while repressing alternative lineage genes and remains essential in mature B-lineage cells (Cobaleda et al 2007).…”

mentioning

confidence: 99%

Pax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia

et al. 2014

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Loss-of-function mutations in hematopoietic transcription factors including PAX5 occur in most cases of B-progenitor acute lymphoblastic leukemia (B-ALL), a disease characterized by the accumulation of undifferentiated lymphoblasts. Although PAX5 mutation is a critical driver of B-ALL development in mice and humans, it remains unclear how its loss contributes to leukemogenesis and whether ongoing PAX5 deficiency is required for B-ALL maintenance. Here we used transgenic RNAi to reversibly suppress endogenous Pax5 expression in the hematopoietic compartment of mice, which cooperates with activated signal transducer and activator of transcription 5 (STAT5) to induce B-ALL. In this model, restoring endogenous Pax5 expression in established B-ALL triggers immunophenotypic maturation and durable disease remission by engaging a transcriptional program reminiscent of normal B-cell differentiation. Notably, even brief Pax5 restoration in B-ALL cells causes rapid cell cycle exit and disables their leukemia-initiating capacity. These and similar findings in human B-ALL cell lines establish that Pax5 hypomorphism promotes B-ALL self-renewal by impairing a differentiation program that can be re-engaged despite the presence of additional oncogenic lesions. Our results establish a causal relationship between the hallmark genetic and phenotypic features of B-ALL and suggest that engaging the latent differentiation potential of B-ALL cells may provide new therapeutic entry points.

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Extensive in vivo self-renewal, long-term reconstitution capacity, and hematopoietic multipotency of Pax5-deficient precursor B-cell clones

Cited by 54 publications

References 36 publications

Transient Notch signaling induces NK cell potential in Pax5‐deficient pro‐B cells

Transient Notch signaling induces NK cell potential in Pax5‐deficient pro‐B cells

A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans

Pax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia

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