PU.1 Functions in a Cell-Autonomous Manner to Control the Differentiation of Multipotential Lymphoid–Myeloid Progenitors

Scott, Edward W.; Fisher, Robert C.; Olson, Marilyn C.; Kehrli, Eli W; Simon, M. Celeste; Singh, Harinder

doi:10.1016/s1074-7613(00)80287-3

Cited by 249 publications

(175 citation statements)

References 29 publications

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“…One strain of PU.1 knock out mice shows defects in erythroid maturation (Scott et al, 1994). Another PU.1 de®cient mouse strain exhibits no apparent defects in erythrocyte development but are de®cient in macrophages, neutrophils, B cells, and T cells compared to wild-type mice (McKercher et al, 1996;Scott et al, 1997). In both strains, however, the Nterminal half of the PU.1 gene is intact in the targeted genome, and in neither case has it been determined whether the N-terminal peptide is expressed.…”

Section: Discussionmentioning

confidence: 99%

GOOSECOID inhibits erythrocyte differentiation by competing with Rb for PU.1 binding in murine cells

Konishi¹,

Tominaga²,

Watanabe³

et al. 1999

Oncogene

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Section: Discussionmentioning

confidence: 99%

GOOSECOID inhibits erythrocyte differentiation by competing with Rb for PU.1 binding in murine cells

Konishi¹,

Tominaga²,

Watanabe³

et al. 1999

Oncogene

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“…Mice homozygous for a null mutation in the PU.1 gene die during fetal development by 18.5 days postcoitum (d.p.c.) and lack B, T, and myeloid progenitors (10,11). PU.1 Ϫ/Ϫ fetal liver contains reduced numbers of multipotential lymphoid-myeloid progenitors (AA4.1 ϩ , Lin Ϫ ).…”

Section: Cells (4)mentioning

confidence: 99%

Analysis of Gene Expression and Ig Transcription in PU.1/Spi-B-Deficient Progenitor B Cell Lines

Schweitzer

DeKoter

2004

The Journal of Immunology

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A number of presumptive target genes for the Ets-family transcription factor PU.1 have been identified in the B cell lineage. However, the precise function of PU.1 in B cells has not been studied because targeted null mutation of the PU.1 gene results in a block to lymphomyeloid development at an early developmental stage. In this study, we take advantage of recently developed PU.1−/−Spi-B−/− IL-7 and stromal cell-dependent progenitor B (pro-B) cell lines to analyze the function of PU.1 and Spi-B in B cell development. We show that contrary to previously published expectations, PU.1 and/or Spi-B are not required for Ig H chain (IgH) gene transcription in pro-B cells. In fact, PU.1−/−Spi-B−/− pro-B cells have increased levels of IgH transcription compared with wild-type pro-B cells. In addition, high levels of Igκ transcription are induced after IL-7 withdrawal of wild-type or PU.1−/−Spi-B−/− pro-B cells. In contrast, we found that Igλ transcription is reduced in PU.1−/−Spi-B−/− pro-B cells relative to wild-type pro-B cells after IL-7 withdrawal. These results suggest that Igλ, but not IgH or Igκ, transcription, is dependent on PU.1 and/or Spi-B. The PU.1−/−Spi-B−/− pro-B cells have other phenotypic changes relative to wild-type pro-B cells including increased proliferation, increased CD25 expression, decreased c-Kit expression, and decreased RAG-1 expression. Taken together, our observations suggest that reduction of PU.1 and/or Spi-B activity in pro-B cells promotes their differentiation to a stage intermediate between late pro-B cells and large pre-B cells.

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“…Spi-1/PU.1 plays an essential role in normal lymphopoiesis and myelopoiesis. It regulates the transcription of many myeloid and B lymphoid genes (for review Moreau-Gachelin, 1994) and its inactivation in mice results in a multilineage defect characterized by an absence of B lymphocytes and macrophages (McKercher et al, 1996;Scott et al, 1997). Although the down regulation of spi-1 during the chemicallyinduced di erentiation of Friend cells suggested that Spi-1 was involved in the di erentiation arrest of the proerythroblast (Schuetze et al, 1992), the role of Spi-1/PU 1 in the transformation of erythroid cells was deduced from the pathology observed in mice overexpressing a spi-1 transgene (Moreau-Gachelin et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Spi-1 transgenic mice develop a clonal erythroleukemia which does not depend on p53 mutation

et al. 1998

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Spi-1 transcriptional activation and wild-type p53 extinction are two oncogenic alterations involved in the malignant transformation of erythroblasts during the Friend acute erythroleukemia. To dissect the contribution of these alterations in the deregulation of the di erentiation and proliferation of erythroblasts, we generated spi-1 transgenic mice. Analysis of these animals revealed that Spi-1 overexpression was directly involved in the block of proerythroblast di erentiation. However, the erythroleukemia that develops in these animals evolved in two steps. During the early step (HS1 step), non tumorigenic proerythroblasts remained strictly dependent upon erythropoietin (Epo) for their survival and proliferation. Later on, Epo-independent and tumorigenic proerythroblasts emerged (HS2 step) suggesting that other oncogenes cooperate with Spi-1 to lead to a fully malignant phenotype. By provirus tagging, we demonstrate that the HS1 step was clonal indicating that a cell selection must occur in vivo. Analysis of the nature of p53 in both the in vivo HS1 and HS2 proerythroblasts and in cultured erythroblastic cell lines showed that ± p53 was normal in the HS1 primary tissues but was mutated in the HS1 cultured cell lines ± p53 was frequently altered in HS2 primary tissues but was found normal in some mice. These data indicate that (i) the blockage of the erythroblast di erentiation by Spi-1 occurs independently of p53 alteration (ii) p53 alteration is not necessary to confer Epo independence and tumorigenicity to spi-1 transgenic proerythroblasts.

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PU.1 Functions in a Cell-Autonomous Manner to Control the Differentiation of Multipotential Lymphoid–Myeloid Progenitors

Cited by 249 publications

References 29 publications

GOOSECOID inhibits erythrocyte differentiation by competing with Rb for PU.1 binding in murine cells

GOOSECOID inhibits erythrocyte differentiation by competing with Rb for PU.1 binding in murine cells

Analysis of Gene Expression and Ig Transcription in PU.1/Spi-B-Deficient Progenitor B Cell Lines

Spi-1 transgenic mice develop a clonal erythroleukemia which does not depend on p53 mutation

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