Interleukin-7 induces N-myc and c-myc expression in normal precursor B lymphocytes.

Morrow, Maureen A.; Lee, Grace; Gillis, S; Yancopouloš, George D.; Alt, Frederick W.

doi:10.1101/gad.6.1.61

Cited by 85 publications

(67 citation statements)

References 45 publications

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“…As expected (32), sense N-myc transcription was found in both cell types. Notably, we found a consistent (n = 3) 10-to 20-fold excess of antisense versus sense transcription across V H J558 gene segments in both cell types (Fig.…”

Section: Resultssupporting

confidence: 85%

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Elements between the IgH variable (V) and diversity (D) clusters influence antisense transcription and lineage-specific V(D)J recombination

Giallourakis

Franklin²,

Guo³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Ig and T-cell receptor (TCR) variable-region gene exons are assembled from component variable (V), diversity (D) and joining (J) gene segments during early B and T cell development. The RAG1/2 endonuclease initiates V(D)J recombination by introducing DNA double-strand breaks at borders of the germ-line segments. In mice, the Ig heavy-chain (IgH) locus contains, from 5′ to 3′, several hundred V H gene segments, 13 D segments, and 4 J H segments within a several megabase region. In developing B cells, IgH variable-region exon assembly is ordered with D to J H rearrangement occurring on both alleles before appendage of a V H segment. Also, IgH V H to DJ H rearrangement does not occur in T cells, even though DJ H rearrangements occur at low levels. In these contexts, V(D)J recombination is controlled by modulating substrate gene segment accessibility to RAG1/2 activity. To elucidate control elements, we deleted the 100-kb intergenic region that separates the V H and D clusters (generating ΔV H -D alleles). In both B and T cells, ΔV H -D alleles initiated high-level antisense and, at lower levels, sense transcription from within the downstream D cluster, with antisense transcripts extending into proximal V H segments. In developing T lymphocytes, activated germ-line antisense transcription was accompanied by markedly increased IgH D-to-J H rearrangement and substantial V H to DJ H rearrangement of proximal IgH V H segments. Thus, the V H -D intergenic region, and likely elements within it, can influence silencing of sense and antisense germ-line transcription from the IgH D cluster and thereby influence targeting of V(D)J recombination. The activity of the common V(D)J recombinase is regulated in several contexts (8, 9). First, V(D)J recombination is regulated in a lineage-specific manner. Thus, Ig variable-region exons are completely assembled in B cells and not in T cells, whereas TCR variable-region exons are assembled in T but not B cells (6). Second, within a given lineage, V(D)J recombination is highly ordered. The IgH locus contains a large cluster of V H segments, a cluster of 13 D segments, and a cluster of 4 J H segments in a several-megabase region (1). In progenitor (pro) B lymphocytes, IgH variable-region exons are assembled via a process in which D to J H rearrangements occur first and on both alleles, followed by appendage of a V H segment to the DJ H complex (10). Direct joining of a V H to a D is not observed, even though permitted by the 12/23 rule (10). Although not strictly ordered, the most Dproximal V H families and, in particular, the most D-proximal V H 81X gene segment, rearrange more frequently than the most distal V H gene families, such as the V H J558 family (11). After assembly of a productive IgH variable-region exon and expression of a μ heavy chain, pro-B cells advance to the precursor (pre) stage at which Ig light-chain (IgL) variable-region assembly occurs. Similarly ordered V(D)J recombination occurs during assembly of TCR variable-region exons in developing T lineage cells (12). F...

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Section: Resultssupporting

confidence: 85%

“…Nuclear run-on analyses were performed as described (32,45). Further details are in SI Materials and Methods and Table S1.…”

Section: Methodsmentioning

confidence: 99%

Elements between the IgH variable (V) and diversity (D) clusters influence antisense transcription and lineage-specific V(D)J recombination

Giallourakis

Franklin²,

Guo³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…N-Myc and c-Myc are both expressed in the earliest B and T lymphocyte progenitors, pro-T and pro-B cells. However, c-Myc is the only Myc family protein expressed at subsequent stages of B and T cell development and in mature B and T cells [2,[10][11][12][13]. c-Myc deficiency in T cell progenitors leads to an early block in T lymphocyte development [14,15].…”

Section: Introductionmentioning

confidence: 99%

Dynamic regulation of c‐Myc proto‐oncogene expression during lymphocyte development revealed by a GFP‐c‐Myc knock‐in mouse

et al. 2008

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Abstractc‐Myc induces widely varying cellular effects, including cell proliferation and cell death. These different cellular effects are determined, in part, by c‐Myc protein expression levels, which are regulated through several transcriptional and post‐transcriptional pathways. c‐Myc transcripts can be detected in cells at all stages of B and T lymphocyte development. However, little is known about c‐Myc protein expression, and how it varies, in developing lymphocytes. Here mice have been generated in which the endogenous c‐Myc locus has been modified (c‐MycG) so that it encodes a GFP‐c‐Myc fusion protein. c‐MycG/G mice are viable, appear normal and exhibit grossly normal lymphocyte development. Flow cytometric analyses revealed significant heterogeneity in c‐Myc protein expression levels in developing c‐MycG/G B and T lymphocytes. GFP‐c‐Myc expression levels were highest in proliferating lymphocytes, suggesting that c‐Myc up‐regulation is important for promoting lymphocyte cell division, and demonstrating that GFP‐c‐Myc expression is a marker of proliferating lymphocytes in vivo.

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“…After birth, expression is restricted to B lymphocytes where N-myc transcripts are present only in preB cells. Upon di erentiation to the mature B cell stage, coincident with completion of immunoglobulin (Ig) gene expression, N-myc expression turns o and remains o (Reth et al, 1985;Zimmerman et al, 1986;Smith et al, 1992;Morrow et al, 1992). The oncogenic potential of the human N-myc gene has been implicated in various tumors including neuroblastoma (Brodeur et al, 1984;Kohl et al, 1984), Wilms' tumor (Nisen et al, 1986), retinoblastoma (Lee et al, 1984), small cell lung carcinoma , medullary thyroid carcinoma (Roncalli et al, 1994), testis (Shuin et al, 1994), brain (Hirvonen et al, 1994), and breast (Mizukami et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Transgenic N-myc mouse model for indolent B cell lymphoma: tumor characterization and analysis of genetic alterations in spontaneous and retrovirally accelerated tumors

et al. 1998

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Little is known about stepwise deregulation of speci®c genes leading to lymphoid malignancy. Aberrant myc gene expression in transgenic mice is correlated with B cell lymphomagenesis. We generated a unique transgenic mouse model in which deregulated murine Em-N-myc transgene expression leads to development of indolent B cell lymphoma. Tumor cells were monoclonal, morphologically mature and surface immunoglobulin expressing B cells. Tumors arose in a disease course and exhibited a cytoarchitectural appearance reminiscent of human follicular lymphoma. Yet tumor cells were staged as preB since they failed to rearrange the immunoglobulin light chain genes. Retroviral insertion mutagenesis analyses of adult transgenic mice infected as newborns with murine leukemia virus revealed decreased disease latency, increased lymphoma incidence and a histologically more mature tumor type. Proviral insertion sites were not equivalent when accelerated Em-N-myc indolent lymphomas were compared to accelerated c-myc preB cell lymphomas. The bcl-2 gene was not disrupted in either spontaneous or provirally accelerated Em-N-myc lymphomas. These ®ndings suggest that tumor progression in N-myc-associated indolent B cell lymphoma can proceed along diverse pathways involving distinctly di erent combinations of deregulated and/or intact genes than those pathways described in highly aggressive forms of myc-related murine preB cell disease.

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Interleukin-7 induces N-myc and c-myc expression in normal precursor B lymphocytes.

Cited by 85 publications

References 45 publications

Elements between the IgH variable (V) and diversity (D) clusters influence antisense transcription and lineage-specific V(D)J recombination

Elements between the IgH variable (V) and diversity (D) clusters influence antisense transcription and lineage-specific V(D)J recombination

Dynamic regulation of c‐Myc proto‐oncogene expression during lymphocyte development revealed by a GFP‐c‐Myc knock‐in mouse

Transgenic N-myc mouse model for indolent B cell lymphoma: tumor characterization and analysis of genetic alterations in spontaneous and retrovirally accelerated tumors

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