Regulation of B Lymphocyte and Macrophage Development by Graded Expression of PU.1

DeKoter, Rodney P.; Singh, Harinder

doi:10.1126/science.288.5470.1439

Cited by 650 publications

(511 citation statements)

References 25 publications

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“…We show in this study that TNF induced increased expression of the myeloid and lymphoid transcription factor, PU.1 [58,59]. The analysis of GATA-1/PU.1 interaction by immunoprecipitation showed that the TNF-mediated increase in PU.1 expression was associated with the formation of the GATA-1/PU.1 complex in the nuclear extracts from EPO-induced HSPCs.…”

Section: Discussionmentioning

confidence: 51%

Tumor necrosis factor alpha-mediated inhibition of erythropoiesis involves GATA-1/GATA-2 balance impairment and PU.1 over-expression

Grigorakaki

Morceau

Chateauvieux

et al. 2011

Biochemical Pharmacology

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Many physiological perturbations can cause anemia. In cancer patients, activation of the immune system leads to the production of proinflammatory cytokines including tumor necrosis factor alpha (TNF), that have been shown to inhibit red-cell production via poorly understood mechanisms. Treatment of anemia by human recombinant erythropoietin (EPO) is strongly suspected to induce tumor growth.This study focuses on the mechanisms involved in TNF-mediated inhibition of erythropoiesis. CD34 + hematopoietic stem/progenitor cells (HSPC) were isolated from human cord blood. Erythropoiesis was achieved in vitro by stimulating cells with EPO. We show that TNF clearly affected erythroid development, as assessed by May-Grünwald/Giemsa staining, flow cytometry analysis and fluorescent microscopy. The amount of hemoglobinproducing cells as well as the expression of GATA-1 target erythro-specific genes (EPO receptor, glycophorin A and globins) was found decreased after TNF treatment of HSPC. In correlation, TNF induced the expression of the transcription factors GATA-2 and PU.1, described as inhibitors of erythropoiesis. In this regard, TNF promoted the formation of the GATA-1/PU.1 complex that has been reported to block the transcriptional activity of GATA-1. Our results clearly demonstrate that TNF prevents EPO-mediated erythropoiesis of HSPC as an early event, by directly affecting erythroid cell development.Keywords: anemia; inflammation; TNF; GATA-1; GATA-2; PU.1Page 3 of 38 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 -3 - IntroductionThe majority of tumors are largely infiltrated by inflammatory cells, such as myelomonocytes and macrophages [1]. In response to the inflammatory environment, these cells produce inflammatory mediators including chemokines and cytokines. These mediators are tightly associated with cancer progression in combination with genetic alterations [2]. One of them, the Tumor Necrosis Factor alpha (TNF), is widely found in the inflammationassociated cancer microenvironment [3][4][5][6]. Interestingly, because TNF is commonly present in cancer and inflammatory diseases, it has been implicated in cancer-and inflammationrelated anemia. Indeed, patients suffering from cancer and chronic inflammation are often anemic [7]. Moreover, in vitro and in vivo studies have led to the conclusion that TNF inhibits hematopoietic progenitors from undergoing erythroid differentiation [8][9][10][11][12][13][14][15]. Anti-TNF treatment is effectively used for the treatment of chronic inflammatory diseases, but leads to increased risk of infection [16,17]. Despite the beneficial effects of anti-TNF, this treatment may promote different types of cancers [18,19].Several events may trigger anemia, including iron deficiency, hemolysis and hemorrhage. In non-hematopo...

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Section: Discussionmentioning

confidence: 51%

Tumor necrosis factor alpha-mediated inhibition of erythropoiesis involves GATA-1/GATA-2 balance impairment and PU.1 over-expression

Grigorakaki

Morceau

Chateauvieux

et al. 2011

Biochemical Pharmacology

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“…In Table 2 the expression of investigated B-cell transcription factors in normal B-cell development is displayed. [12][13][14][15][16][17][18][19][20][21][22][23] Early B-Cell Transcription Factors: Pax-5 and PU.1 Expression…”

Section: Resultsmentioning

confidence: 99%

“…Consistent with data from literature, PU.1 expression was observed in admixed histiocytes. 16 Mature B-Cell Transcription Factors: Oct2, BOB.1 and Bcl-6 Expression BOB.1 and Oct2 were detectable in all B-cell populations present in pseudo B-cell lymphomas and tonsils including mantle B-cells, germinal center B-cells and plasma cells. Expression of both Oct2 and BOB.1 was observed in 90% or more of the tumor cells in all 11 cases of primary cutaneous large B-cell lymphoma, leg type.…”

Section: Transcription Factors In Cutaneous B-cell Lymphoma Jj Hoefnamentioning

confidence: 99%

Expression of B-cell transcription factors in primary cutaneous B-cell lymphoma

et al. 2006

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Expression patterns of eight transcription factors involved in different stages of B-cell development were investigated in a large group of primary cutaneous B-cell lymphomas and compared with expression patterns during normal B-cell development. The following transcription factors were investigated: Pax-5, PU.1, Oct2, BOB.1, Bcl-6, Mum1/IRF4, Blimp-1 and FOXP1. Primary cutaneous large B-cell lymphomas, leg type showed aberrant coexpression of Bcl-6 and Mum1/IRF4 and in addition strong expression of FOXP1. Expression of FOXP1 and Mum1/IRF4 strongly suggests an activated B-cell type of origin. In contrast, primary cutaneous follicle center lymphomas showed expression of Bcl-6, Pax-5, PU.1, Oct2 and BOB.1, but not of Mum1/IRF4, Blimp-1 and FOXP1. Primary cutaneous marginal zone B-cell lymphoma showed expression of Pax-5, PU.1, Oct2 and BOB.1, but not Bcl-6 by the neoplastic B-cells, and Mum1/IRF4 and Blimp-1 by the neoplastic plasma cells. In conclusion, in primary cutaneous follicle center lymphoma and primary cutaneous marginal zone B-cell lymphoma expression patterns were observed similar to their supposed benign counterparts, germinal center B-cells and postgerminal center B-cells, respectively, which might reflect their indolent clinical behaviour and excellent prognosis. In contrast, the activated B-cell expression pattern in the group of primary cutaneous large B-cell lymphoma, leg type may contribute to its poor prognosis and Mum1/IRF4 and FOXP1 may serve as additional diagnostic markers for this type of primary cutaneous B-cell lymphoma.

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“…These developmental steps are controlled by diverse cytokines and transcription factors cooperating to achieve efficient generation of mature lymphocytes 154 . In early stages, both PU.1 and Ikaros control the balance between myeloid or lymphoid commitment of MMPs through regulation of different signaling receptors (FLT3, c-KIT and IL-7R) [157][158][159] . More committed, earliest B cell progenitor transition to pro-B cell depends on addi-tional transcription factors (E2A, EBF, PAX5 and BCL11A), which coordinately activate appropriate Bcell expression programs and immunoglobulin heavychain gene rearrangements [160][161][162][163][164][165] .…”

Section: Do Lymphoid Malignancies Arise From Mutations That Deregulatmentioning

confidence: 99%

Somatic stem cells and the origin of cancer

2006

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647Most human cancers derive from a single cell targeted by genetic and epigenetic alterations that initiate malignant transformation. Progressively, these early cancer cells give rise to different generations of daughter cells that accumulate additional mutations, acting in concert to drive the full neoplastic phenotype 1,2 . As we have currently deciphered many of the gene pathways disrupted in cancer, our knowledge about the nature of the normal cells susceptible to transformation upon mutation has remained more elusive. Adult stem cells are those that show long-term replicative potential, together with the capacities of self-renewal and multi-lineage differentiation. These stem cell properties are tightly regulated in normal development, yet their alteration may be a critical issue for tumorigenesis. This concept has arisen from the striking degree of similarity noted between somatic stem cells and cancer cells, including the fundamental abilities to self-renew and differentiate. Given these shared attributes, it has been proposed that cancers are caused by transforming mutations occurring in tissue-specific stem cells 3-9 . This hypothesis has been functionally supported by the observation that among all cancer cells within a particular tumor, only a minute cell fraction has the exclusive potential to regenerate the entire tumor cell population 3,10-13 ; these cells with stem-like properties have been termed cancer stem cells. Cancer stem cells can originate from mutation in normal somatic stem cells that deregulate their physiological programs. Alternatively, mutations may target more committed progenitor cells or even mature cells, which become reprogrammed to acquire stem-like functions 14,15 In any case, mutated genes should promote expansion of stem/progenitor cells, thus increasing their predisposition to cancer development by expanding self-renewal and pluripotency over their normal tendency towards relative quiescency and proper differentiation.

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Regulation of B Lymphocyte and Macrophage Development by Graded Expression of PU.1

Cited by 650 publications

References 25 publications

Tumor necrosis factor alpha-mediated inhibition of erythropoiesis involves GATA-1/GATA-2 balance impairment and PU.1 over-expression

Tumor necrosis factor alpha-mediated inhibition of erythropoiesis involves GATA-1/GATA-2 balance impairment and PU.1 over-expression

Expression of B-cell transcription factors in primary cutaneous B-cell lymphoma

Somatic stem cells and the origin of cancer

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