Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation

Iwasaki, Hiromi; Somoza, Chamorro; Shigematsu, Hirokazu; Duprez, Estelle; Iwasaki-Arai, Junko; Mizuno, Shin Ichi; Arinobu, Yojiro; Geary, Kristin; Zhang, Pu; Dayaram, Tajhal; Fenyus, Maris; Elf, Shannon; Chan, Susan; Kastner, Philippe; Huettner, Claudia S.; Murray, Richard M.; Tenen, Daniel G.; Akashi, Koichi

doi:10.1182/blood-2005-03-0860

Cited by 366 publications

(360 citation statements)

References 66 publications

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“…Deletion of PU.1 in mice results in a relatively late embryonic lethality (around E17.5). 32 PU.1 À/À mice have a reduced pool of HSC and progenitors [33][34][35] leading to the loss of mature macrophages, neutrophils, B-cells, T-cells and mast cells 32,36,37 and to the mild defect of erythropoiesis. 33 Interestingly, PU.1 null hematopoietic progenitors express diminished levels of the myeloid growth-factor receptors (G, GM, M) yet can be expanded in vitro upon addition of the IL-3 cytokine indicating that their growth survival can be regulated in a PU.1-independent fashion.…”

Section: Pu1 and Its Role In Hematopoiesismentioning

confidence: 99%

The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis

2010

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Hematopoiesis is coordinated by a complex regulatory network of transcription factors and among them PU.1 (Spi1, Sfpi1) represents a key molecule. This review summarizes the indispensable requirement of PU.1 during hematopoietic cell fate decisions and how the function of PU.1 can be modulated by protein-protein interactions with additional factors. The mutual negative regulation between PU.1 and GATA-1 is detailed within the context of normal and leukemogenic hematopoiesis and the concept of 'differentiation therapy' to restore normal cellular differentiation of leukemic cells is discussed.

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Section: Pu1 and Its Role In Hematopoiesismentioning

confidence: 99%

The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis

2010

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“…Besides its role in myelopoiesis and B lymphopoiesis, 1,2 Spi-1/PU.1 participates to the self-renewal of hematopoietic stem cells. [3][4][5][6] PU.1 is expressed in erythroid progenitors and is silenced at an early stage of both fetal and adult erythropoiesis. 7,8 With regard to its role in erythropoiesis, conflicting hypotheses are reported.…”

Section: Introductionmentioning

confidence: 99%

Spi-1/PU.1 participates in erythroleukemogenesis by inhibiting apoptosis in cooperation with Epo signaling and by blocking erythroid differentiation

Rimmelé

Kosmider

Mayeux

et al. 2006

Blood

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Overexpression of the transcription factor Spi-1/PU.1 in mice leads to acute erythroleukemia characterized by a differentiation block at the proerythroblastic stage. In this study, we made use of a new cellular system allowing us to reach graded expression of Spi-1 in preleukemic cells to dissect mechanisms of Spi-1/ PU-1 in erythroleukemogenesis. This system is based on conditional production of 1 or 2 spi-1-interfering RNAs stably inserted into spi-1 transgenic proerythroblasts. We show that Spi-1 knock-down was sufficient to reinstate the erythroid differentiation program. This differentiation process was associated with an exit from the cell cycle. Evidence is provided that in the presence of erythropoietin (Epo), Spi-1 displays an antiapoptotic role that is independent of its function in blocking erythroid differentiation. IntroductionThe ETS family transcription factor Spi-1/PU.1 plays a crucial role in hematopoiesis by determining cell fate through a temporal and spatial control of its expression and activity. Besides its role in myelopoiesis and B lymphopoiesis, 1,2 Spi-1/PU.1 participates to the self-renewal of hematopoietic stem cells. 3-6 PU.1 is expressed in erythroid progenitors and is silenced at an early stage of both fetal and adult erythropoiesis. 7,8 With regard to its role in erythropoiesis, conflicting hypotheses are reported. Fisher et al 9,10 brought argument, suggesting that PU.1 is required for erythropoiesis in adult bone marrow but not in fetal liver. Others showed that PU.1 is involved in the self-renewal of fetal erythroid progenitors, 7 whereas its role in erythroid progenitors from the adult seemed to be excluded. 5 A dysregulation of PU.1 activity can lead to murine malignant hemopathies. Rosenbauer et al, 11 by creating a hypomorphic function, reduced PU.1 expression by 80%, and established an association between PU.1 and the occurrence of acute myeloid leukemia (AML). This report led to the concept that a decrease to a critical threshold level of PU.1 activity, rather than a complete abrogation, contributes to AML pathogenesis. Other publications describing deletion of one PU.1 allele associated with mutations of the other allele leading to reduction in the function of the protein corroborated this paradigm. 12,13 However, a recent study in which the function of PU.1 was examined in adult hematopoiesis using conditional gene targeting describes the development of AML in the absence of PU.1 expression. 14 In contrast to the myeloid lineage, a high expression of spi-1 is oncogenic in the erythroid lineage. 15 In transgenic mice, Spi-1 overexpression leads to the development of severe anemia and hepatosplenomegaly resulting from the proliferation of proerythroblasts blocked in differentiation. 16 At the disease onset, survival and growth of spi-1 transgenic proerythroblasts remain under erythropoietin (Epo) control. Later on, spi-1-transgenic proerythroblasts lose their Epo requirement for proliferation and become tumorigenic. This malignant phenotype requires additional genetics e...

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“…First, there are PU.1-binding sites in many B cell-specific genes (15)(16)(17)(18)(19), including all of the Ig loci, such as the IgH intronic enhancer and 3Ј regulatory regions, the Ig 3Ј enhancer, and the Ig 2-4 enhancer (20 -23). Second, PU.1 is required for the generation of lymphoid progenitors, and therefore no B cells are detected in PU.1 Ϫ/Ϫ fetal livers (24,25). However, conditional knockout studies indicate that PU.1 is not required for the continued survival and differentiation of B cells once they are generated (24,26,27).…”

mentioning

confidence: 99%

“…Second, PU.1 is required for the generation of lymphoid progenitors, and therefore no B cells are detected in PU.1 Ϫ/Ϫ fetal livers (24,25). However, conditional knockout studies indicate that PU.1 is not required for the continued survival and differentiation of B cells once they are generated (24,26,27). One of the consequences of PU.1 deletion in committed B cells is a switch from a B-2 to a B-1 phenotype (27).…”

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confidence: 99%

Spi-C Has Opposing Effects to PU.1 on Gene Expression in Progenitor B Cells

Schweitzer

Huang

Kamath

et al. 2006

The Journal of Immunology

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The Ets transcription factor Spi-C, expressed in B cells and macrophages, is closely related to PU.1 and has the ability to recognize the same DNA consensus sequence. However, the function of Spi-C has yet to be determined. The purpose of this study is to further examine Spi-C activity in B cell development. First, using retroviral vectors to infect PU.1−/− fetal liver progenitors, Spi-C was found to be inefficient at inducing cytokine-dependent proliferation and differentiation of progenitor B (pro-B) cells or macrophages relative to PU.1 or Spi-B. Next, Spi-C was ectopically expressed in fetal liver-derived, IL-7-dependent pro-B cell lines. Wild-type (WT) pro-B cells ectopically expressing Spi-C (WT-Spi-C) have several phenotypic characteristics of pre-B cells such as increased CD25 and decreased c-Kit surface expression. In addition, WT-Spi-C pro-B cells express increased levels of IgH sterile transcripts and reduced levels of expression and transcription of the FcγRIIb gene. Gel-shift analysis suggests that Spi-C, ectopically expressed in pro-B cells, can bind PU.1 consensus sites in the IgH intronic enhancer and FcγRIIb promoter. Transient transfection analysis demonstrated that PU.1 functions to repress the IgH intronic enhancer and activate the FcγRIIb promoter, while Spi-C opposes these activities. WT-Spi-C pro-B cells have reduced levels of dimethylation on lysine 9 of histone H3 within the IgH 3′ regulatory region, indicating that Spi-C can contribute to removal of repressive features in the IgH locus. Overall, these studies suggest that Spi-C may promote B cell differentiation by modulating the activity of PU.1-dependent genes.

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Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation

Cited by 366 publications

References 66 publications

The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis

The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis

Spi-1/PU.1 participates in erythroleukemogenesis by inhibiting apoptosis in cooperation with Epo signaling and by blocking erythroid differentiation

Spi-C Has Opposing Effects to PU.1 on Gene Expression in Progenitor B Cells

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