Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow.

Hardy, Richard R.; Carmack, Condie E.; Shinton, Susan A.; Kemp, John D.; Hayakawa, Kyoko

doi:10.1084/jem.173.5.1213

Cited by 1,488 publications

(1,201 citation statements)

References 48 publications

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“…BM B220 + cells from leukemic mice were negative for IgM and IgD and uniformly over-expressed CD19 and BP-1, while CD34, CD135, CD21/35 and CD79b were not detected and only few cells expressed CD25 and Sca-1 (Fig 1B and S1C). B220, CD24, CD43, CD93 and CD127 expression levels of the abnormal cells were similar to those of control precursor B cells (B220 int CD43 hi ) [15].…”

Section: Statisticssupporting

confidence: 58%

Constitutive Kit activity triggers B-cell acute lymphoblastic leukemia-like disease in mice

Weidemann

Behrendt

Schoedel

et al. 2017

Experimental Hematology

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Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and is of pro-or pre-B cell origin in most cases. The receptor tyrosine kinase KIT is expressed by hematopoietic stem and precursor cells. Gain-of-function mutations of KIT cause systemic mastocytosis, which is characterized by abnormal accumulations of mast cells. We previously reported a mouse model of mastocytosis based on conditional expression of a constitutively active Kit protein. Half of these animals developed leukemic disease of B lineage origin. Herein, we report that this condition bears striking similarities to human B-ALL. The immuno-phenotype of the leukemic cells was compatible with a pro-B cell origin, as was the finding of immunoglobulin heavy chain gene rearrangements in all cases, whereas light chain loci were mostly not rearranged. Leukemogenesis was independent of pre-B cell receptor expression.Primary leukemic cells and permanent cell lines derived from these were serially transplantable and rapidly killed the recipients. In few animals, the leukemia was of T cell origin with abnormal CD4/8 double positive T cell precursors dominating in the circulation. In summary, we report a novel ALL mouse model that may prove useful for in vivo drug testing and identification of novel oncogenic mutations and principles.

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Section: Statisticssupporting

confidence: 58%

Constitutive Kit activity triggers B-cell acute lymphoblastic leukemia-like disease in mice

Weidemann

Behrendt

Schoedel

et al. 2017

Experimental Hematology

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“…While the pre-BCR is expressed on large pre-BII cells, the IL-7Ra chain is expressed on all cell stages from the common lymphoid progenitor (CLP) up to, and including, the pre-BII cells [2, 30,31]. Hence, their expression overlaps at the pre-BII cell stage.…”

Section: Introductionmentioning

confidence: 99%

“…Expansion at the pre-BII stage is dependent on the expression of the pre-BCR. While a lack of the transmembrane region of the lH chain (lMT) leads to a complete block at the pre-BI stage during B cell development and, consequently, a lack of pre-BII cell expansion [26], deficiency in SLC or its components (k5 or VpreB1/VpreB2) leads to an incomplete block in B cell development, resulting in an enriched pre-BI and a reduced pre-BII cell population [27][28][29].While the pre-BCR is expressed on large pre-BII cells, the IL-7Ra chain is expressed on all cell stages from the common lymphoid progenitor (CLP) up to, and including, the pre-BII cells [2,30,31]. Hence, their expression overlaps at the pre-BII cell stage.…”

mentioning

confidence: 99%

Both the pre-BCR and the IL-7Rα are essential for expansion at the pre-BII cell stagein vivo

et al. 2005

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During B cell development, proliferative expansion takes place after expression of the pre-BCR. At this pre-BII cell stage, the IL-7Ra is also expressed. Some in vitro studies suggest that pre-BCR-dependent expansion relies on the IL-7Ra, and others that it does not. It has also been suggested that the pre-BCR mediates down-regulation of the IL7Ra. However, the in vivo relationship between the pre-BCR and the IL-7Ra has not been previously examined. Here, we have investigated this by establishing mice lacking both receptors. Our results show that in the absence of the IL-7Ra, the pre-BII population is reduced, as previously seen in mice lacking the pre-BCR, demonstrating that the IL-7Ra is important at this stage. A deficiency in both receptors results in a further reduction of the pre-BII cell population. We conclude that both the IL-7Ra and the pre-BCR are required for optimal pre-BII cell expansion. Furthermore, IL-7Ra expression levels are normal in pre-BCR-deficient mice, suggesting that the pre-BCR does not mediate its down-regulation. As a consequence of the absence of both receptors, the peripheral B cell pool is severely depleted, resulting in atypical splenic B cell structures and reduced serum Ig levels. IntroductionB lymphopoiesis takes place in the fetal liver and, postnatally, in the BM [1][2][3]. During early BM B cell development, critical checkpoints occur firstly after Ig heavy (H)-chain DJ H rearrangement and secondly after successful VDJ H rearrangement. Due to the inherent imprecision of the rearrangement process, each of these is followed by proliferative expansion at the pre-BI (DJ H ) and large pre-BII (VDJ H ) cell stages, which results in an increase in cell numbers and, consequently, the Ig repertoire. Functional VDJ H -rearrangement leads to expression of the lH chain, which, together with the surrogate light chain (SLC, comprised of VpreB and k5) [4, 5], forms the pre-B cell receptor (pre-BCR) [6][7][8]. After subsequent Ig light (L)-chain recombination, although not followed by an expansion phase, the end result is the production of large numbers of immature B cells, each carrying a unique BCR (IgM) on the cell surface. Immature B cells migrate to the spleen, where they mature and co-express IgD [9].Expansion at the pre-BI cell stage has been shown, both in vitro [10][11][12][13] and in vivo [14][15][16][17][18][19][20][21], to depend on the IL-7Ra [22]. Mice deficient in the IL-7Ra chain show a block in B cell development at the pre-BI stage. Although this block is complete in adult IL-7Ra -/-mice, Leukocyte signalingThe last two authors contributed equally to this work. [20,21]. The IL-7Ra chain heterodimerizes with the common gamma (c C ) chain [22,23] to form the receptor for IL-7, while together with the thymic stromal lymphopoietin (TSLP) receptor chain [24,25], it forms the receptor for TSLP. Expansion at the pre-BII stage is dependent on the expression of the pre-BCR. While a lack of the transmembrane region of the lH chain (lMT) leads to a complete block at the pre-BI stag...

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“…[11][12][13][14] The phenotypes of the progenitors have been well characterized on the basis of their rearrangement status of immunoglobulin (Ig) genes and growth factor requirement. 15,16 In addition, the differentiation mechanisms have been studied at the level of transcription factors. 17,18 Again, in contrast, little information is available for the late stages of human B-lymphopoiesis.…”

Section: Introductionmentioning

confidence: 99%

Culture system for extensive production of CD19+IgM+ cells by human cord blood CD34+ progenitors

et al. 1998

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Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow.

Cited by 1,488 publications

References 48 publications

Constitutive Kit activity triggers B-cell acute lymphoblastic leukemia-like disease in mice

Constitutive Kit activity triggers B-cell acute lymphoblastic leukemia-like disease in mice

Both the pre-BCR and the IL-7Rα are essential for expansion at the pre-BII cell stagein vivo

Culture system for extensive production of CD19+IgM+ cells by human cord blood CD34+ progenitors

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