Dynamic regulation of PU.1 expression in multipotent hematopoietic progenitors

Nutt, Stephen L.; Metcalf, Donald; D’Amico, Angela; Polli, Matthew; Wu, Li

doi:10.1084/jem.20041535

Cited by 287 publications

(302 citation statements)

References 48 publications

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“…7 These activities are transient because Spi-1 is rapidly silenced during normal erythroid differentiation. 7,8 Our results indicate that Spi-1 renewal and antiapoptotic activities can be functional in engaged erythroid cells from adult mice when its expression is enforced and that these activities may be implicated in the conversion of a normal into a preleukemic proerythroblast. The mechanisms controlled by Spi-1 and responsible for protection against apoptosis in the preleukemic proerythroblasts remain to be determined.…”

Section: Discussionmentioning

confidence: 91%

“…[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. Fisher et al 9,10 brought argument, suggesting that PU.1 is required for erythropoiesis in adult bone marrow but not in fetal liver.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 91%

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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“…PU.1 is expressed in mature monocytes, granulocytes, B and NK cells yet absent in T cells, reticulocytes and megakaryocytes. 19,20 The PU.1 gene itself is transcriptionally regulated by several mechanisms. The proximal promoter of Spi1 contains binding sites for PU.1 indicating a self autonomous regulatory mechanism of gene expression 21 as well as binding sites for Oct-1, Sp1, GATA-1 and Spi-B, which likely mediate initial regulation (activation or repression) of PU.1 during hematopoietic development.…”

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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“…We have developed a high-efficiency system in which to examine the function of PU.1 in adult hematopoiesis using conditional gene targeting (20,21). This system uses the MxCre transgene (22), where Cre recombinase is induced in response to polyinosinic acid͞polycytidylic acid (poly IC) injections in vivo to conditionally delete the DNA-binding Ets domain (exon 5) of PU.1.…”

mentioning

confidence: 99%

Inactivation of PU.1 in adult mice leads to the development of myeloid leukemia

Metcalf

Dakic

Mifsud

et al. 2006

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

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Genetically primed adult C57BL mice were deleted of exon 5 of the gene encoding the transcription factor PU.1 by IFN activation of Cre recombinase. After a 13-week delay, conditionally deleted (PU.1 ؊/؊ ) mice began dying of myeloid leukemia, and 95% of the mice surviving from early postinduction death developed transplantable myeloid leukemia whose cells were deleted of PU.1 and uniformly Gr-1 positive. The leukemic cells formed autonomous colonies in semisolid culture with varying clonal efficiency, but colony formation was enhanced by IL-3 and sometimes by granulocyte-macrophage colony-stimulating factor. Nine of 13 tumors analyzed had developed a capacity for autocrine IL-3 or granulocyte-macrophage colony-stimulating factor production, and there was evidence of rearrangement of the IL-3 gene. Acquisition of autocrine growth-factor production and autonomous growth appeared to be major events in the transformation of conditionally deleted PU.1 ؊/؊ cells to fully developed myeloid leukemic populations.mouse ͉ transplantation ͉ growth-factor production

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Dynamic regulation of PU.1 expression in multipotent hematopoietic progenitors

Cited by 287 publications

References 48 publications

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

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

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

Inactivation of PU.1 in adult mice leads to the development of myeloid leukemia

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