Direct interaction of PU.1 with oncogenic transcription factors reduces its serine phosphorylation and promoter binding

Seshire, Anita; Rößiger, T; Frech, Miriam; Beez, S; Hagemeyer, H; Puccetti, Elena

doi:10.1038/leu.2011.331

Cited by 13 publications

(15 citation statements)

References 49 publications

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“…D ). Given recent findings implicating Pu.1 phosphorylation in the transcriptional activation of terminal myeloid‐specific gene programs, we postulate this to be a previously unrecognized mechanism by which Nf1 haploinsufficiency engenders myeloid lineage commitment, thereby promoting osteoclastogenesis and hyperresorptive activity.…”

Section: Resultsmentioning

confidence: 86%

“…In fact, recent studies suggest that phosphorylation of Pu.1 plays a central role in modulating its DNA binding affinity, (37,46) and is thereby critical to its ability to activate myeloid-specific gene programs that promote terminal differentiation. (39,40) For instance, although human myeloid leukemic cell lines have been shown to overexpress Pu.1, (47) the transcript levels of Pu.1-dependent myeloid genes, such as CD11b and c-fms, are relatively low by comparison. (48,49) Carey and colleagues (37) showed that this discrepancy between Pu.1 expression level and transcriptional activity depends on the phosphorylation status of Pu.1, whereby Pu.1 phosphorylation induced by tetradecanoylphorbol-13 acetate (TPA) led to growth arrest in leukemic cells.…”

Section: Discussionmentioning

confidence: 99%

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Nf1 Haploinsufficiency Alters Myeloid Lineage Commitment and Function, Leading to Deranged Skeletal Homeostasis

Rhodes

Yang

Dong

et al. 2015

Journal of Bone and Mineral Research

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While nullizygous loss of NF1 leads to myeloid malignancies, haploinsufficient loss of NF1 (Nf1) has been shown to contribute to osteopenia and osteoporosis which occurs in approximately 50 percent of neurofibromatosis type 1 (NF1) patients. Bone marrow mononuclear cells of haploinsufficient NF1 patients and Nf1+/- mice exhibit increased osteoclastogenesis and accelerated bone turnover, however the culprit hematopoietic lineages responsible for perpetuating these osteolytic manifestations have yet to be elucidated. Here we demonstrate that conditional inactivation of a single Nf1 allele within the myeloid progenitor cell population (Nf1-LysM) is necessary and sufficient to promote multiple osteoclast gain-in-functions, resulting in enhanced osteoclastogenesis and accelerated osteoclast bone lytic activity in response to pro-resorptive challenge in vivo. Surprisingly, mice conditionally Nf1 heterozygous in mature, terminally differentiated osteoclasts (Nf1-Ctsk) do not exhibit any of these skeletal phenotypes, indicating a critical requirement for Nf1 haploinsufficiency at a more primitive/progenitor stage of myeloid development in perpetuating osteolytic activity. We further identified p21Ras dependent hyper-phosphorylation of Pu.1 within the nucleus of Nf1 haploinsufficent myelomoncytic osteoclast precursors, providing a novel therapeutic target for the potential treatment of NF1 associated osteolytic manifestations.

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Section: Resultsmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Nf1 Haploinsufficiency Alters Myeloid Lineage Commitment and Function, Leading to Deranged Skeletal Homeostasis

Rhodes

Yang

Dong

et al. 2015

Journal of Bone and Mineral Research

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“…In particular, restoring sufficient levels of PU.1 functional protein can partially overcome the maturation arrest mediated by the PML/RARA and PLZF/RARA fusion proteins [36]. Of note, PU.1 overexpression does not per se interfere with LICs and does not cure the disease [17]. Factors that induce transcriptional activation in PML/RARA-transformed cells suffice just to initiate differentiation, whereas only a profound and long-lasting deprivation of PML/RARA function causes the loss of clonogenic activity, dissociating simple maturation of still leukemogenic blasts from true eradication of LICs [14].…”

Section: Discussionmentioning

confidence: 99%

“…In the myeloid compartment, PU.1, an ETS transcription factor known to regulate myeloid differentiation, has a well-established role in leukemia suppression [16, 17]. Silencing of PU.1 in the adult hematopoietic tissue produces dysfunctional stem cells and impairs granulopoiesis, by inducing a maturation block [18].…”

Section: Introductionmentioning

confidence: 99%

PML/RARa inhibits PTEN expression in hematopoietic cells by competing with PU.1 transcriptional activity

et al. 2016

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Acute promyelocitic leukemia (APL) is characterized by the pathognomonic presence in leukemic blasts of the hybrid protein PML/RARA, that acts as a transcriptional repressor impairing the expression of genes that are critical to myeloid differentiation. Here, we show that primary blasts from APL patients express lower levels of the oncosuppressor protein PTEN, as compared to blast cells from other AML subtypes or normal bone marrow, and demonstrate that PML-RARA directly inhibits PTEN expression. We show that All-Trans Retinoic Acid (ATRA) triggers in APL cells an active chromatin status at the core regulatory region of the PTEN promoter, that allows the binding of the myeloid-regulating transcription factor PU.1, and, in turn, the transcriptional induction of PTEN. ATRA, via PML/RARA degradation, also promotes PTEN nuclear re-localization and decreases expression of the PTEN target Aurora A kinase. In conclusion, our findings support the notion that PTEN is one of the primary targets of PML/RARA in APL

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“…Accordingly, altered PU.1 function is possibly involved in leukemogenesis, as the PU.1 gene mutation has been described in certain patients with AML (10). Furthermore, certain oncogenic fusion proteins, such as AML1-eight twenty-one and promyelocytic leukemia-retinoic acid receptor α, are also associated PU.1 affects proliferation of the human acute myeloid leukemia U937 cell line by directly regulating MEIS1 with PU.1 inhibition (11)(12)(13)(14). Thus, as a tumor suppressor, PU.1 expression facilitates commitment to myeloid differentiation and its downregulation may be crucial in the pathogenesis of AML.…”

Section: Introductionmentioning

confidence: 99%

PU.1 affects proliferation of the human acute myeloid leukemia U937 cell line by directly regulating MEIS1

Zhou

Zhang

Wang³

et al. 2015

Oncology Letters

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Direct interaction of PU.1 with oncogenic transcription factors reduces its serine phosphorylation and promoter binding

Cited by 13 publications

References 49 publications

Nf1 Haploinsufficiency Alters Myeloid Lineage Commitment and Function, Leading to Deranged Skeletal Homeostasis

Nf1 Haploinsufficiency Alters Myeloid Lineage Commitment and Function, Leading to Deranged Skeletal Homeostasis

PML/RARa inhibits PTEN expression in hematopoietic cells by competing with PU.1 transcriptional activity

PU.1 affects proliferation of the human acute myeloid leukemia U937 cell line by directly regulating MEIS1

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