Is PU.1 a dosage-sensitive regulator of haemopoietic lineage commitment and leukaemogenesis?

Dakic, Aleksandar; Wu, Li; Nutt, Stephen L.

doi:10.1016/j.it.2007.01.006

Cited by 64 publications

(63 citation statements)

References 57 publications

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“…PU.1 and its close relative Spi-B are members of the Ets domain-containing transcription factor family that is expressed in hematopoietic cells, including B cells, T cells, and macrophages (27). The specific deletion of PU.1 in the B lineage did not markedly affect B cell development (28).…”

Section: Discussionmentioning

confidence: 99%

Lyn Signaling To Upregulate GANP Is Critical for the Survival of High-Affinity B Cells in Germinal Centers of Lymphoid Organs

Kuwahara

Nakaya

Phimsen

et al. 2012

The Journal of Immunology

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Signals through BCR and costimulatory molecules play essential roles in selecting high-affinity B cells with Ig V-region mutations in the germinal centers (GCs) of peripheral lymphoid organs. Lyn-deficient (lyn−/−) mice show impaired BCR signal triggering for cell proliferation and GC formation, causing hyper-IgM, and display autoimmunity after aging. In this study, we demonstrate that Lyn-mediated signaling to upregulate GANP is essential for the survival of mature GC-like (mGC) B cells with high-affinity type BCR mutations upon Ag immunization. Transgenic ganp expression into lyn−/− mice did not recover the Lyn-deficient phenotype with regard to B cell differentiation, serum Igs, and impaired GC formation in spleens after immunization with nitrophenyl-chicken γ-globulin, but it markedly rescued cell survival of mGC B cells by suppressing DNA damage, thereby increasing the frequency of the Trp33-to-Leu mutation in the IgVH-186.2 region and affinity maturation of nitrophenyl-binding B cells. GANP may play a critical role in Lyn-mediated signaling for the selection of high-affinity B cells in peripheral lymphoid organs.

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Section: Discussionmentioning

confidence: 99%

Lyn Signaling To Upregulate GANP Is Critical for the Survival of High-Affinity B Cells in Germinal Centers of Lymphoid Organs

Kuwahara

Nakaya

Phimsen

et al. 2012

The Journal of Immunology

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“…Among the regulatory hematopoietic factors, PU.1 is perhaps one of the most critical because it controls both lymphopoiesis and myelopoiesis (11,15,18), depending on its level of expression, with a lower level favoring B lymphoid commitment and differentiation, and with a higher level favoring the maturation of macrophages and granulocytes (19,48). The myeloid regulation by PU.1 seems to occur at the terminal differentiation stage rather than at the commitment stage of the precursor cell (49).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, mice lacking PU.1 do not make mature macrophages, functional granulocytes, B cells, and T cells (11)(12)(13)(14)(15). It was proposed that the choice of hematopoietic progenitors for a specific lineage is determined by graded levels of PU.1 and that high or medium PU.1 level favors respectively macrophage or granulocyte differentiation, whereas lower concentrations are sufficient for B-cell development (16)(17)(18)(19)(20). The regulation of myeloid or lymphoid promoters by PU.1 is modulated by its interaction with other transcription factors, such as GATA-1, C/EBPs, RUNX1, c-Jun, IRFs, and B cell-specific activator protein (21)(22)(23)(24)(25), suggesting that the role of PU.1 in the hematopoietic lineage commitment is determined not only by PU.1 concentration but also by interacting partner factors.…”

Section: Introductionmentioning

confidence: 99%

EVI1 Impairs Myelopoiesis by Deregulation of PU.1 Function

et al. 2009

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EVI1 is an oncogene inappropriately expressed in the bone marrow (BM) of f10% of myelodysplastic syndrome (MDS) patients. This disease is characterized by severe anemia and multilineage myeloid dysplasia that are thought to be a major cause of mortality in MDS patients. We earlier reported on a mouse model that constitutive expression of EVI1 in the BM led to fatal anemia and myeloid dysplasia, as observed in MDS patients, and we subsequently showed that EVI1 interaction with GATA1 blocks proper erythropoiesis. Whereas this interaction could provide the basis for the erythroid defects in EVI1-positive MDS, it does not explain the alteration of myeloid differentiation. Here, we have examined the expression of several genes activated during terminal myelopoiesis in BM cells and identified a group of them that are altered by EVI1. A common feature of these genes is their regulation by the transcription factor PU

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“…36,38,39 Conditional deletion of the PU.1 gene in adult bone marrow progenitors showed its requirement for both monocyte and lymphoid progeny whereas granulocyticlike cells were increased indicating that PU.1 may inhibit adult in vivo granulopoiesis at latter stages of development. 34,40 Similarly, PU.1 has only a minor function in advanced differentiation states of B cells 25,34,35,[41][42][43] and is not required in mature T cells. [44][45][46] Collectively the above-mentioned facts reveal an important and crucial role of PU.1 as a primary transcriptional determinant of hematopoietic cell fate with current evidence showing its substantial role in the cell fate control of HSC and progenitor populations rather than the maturation of terminally differentiated cells.…”

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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Is PU.1 a dosage-sensitive regulator of haemopoietic lineage commitment and leukaemogenesis?

Cited by 64 publications

References 57 publications

Lyn Signaling To Upregulate GANP Is Critical for the Survival of High-Affinity B Cells in Germinal Centers of Lymphoid Organs

Lyn Signaling To Upregulate GANP Is Critical for the Survival of High-Affinity B Cells in Germinal Centers of Lymphoid Organs

EVI1 Impairs Myelopoiesis by Deregulation of PU.1 Function

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

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