PU.1 Mimic Synthetic Peptides Selectively Bind with GATA-1 and Allow c-Jun PU.1 Binding to Enhance Myelopoiesis

Raghav, Pawan Kumar; Gangenahalli, Gurudutta

doi:10.2147/ijn.s303235

Cited by 10 publications

(2 citation statements)

References 61 publications

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“…Indeed, the AP-1 factors c-Jun and JunB are also critical interacting partners with PU.1 that also regulate myeloid differentiation (including PU.1 expression) ( Steidl et al, 2006 ; Raghav et al, 2018 ; Zhao et al, 2022 ). PU.1 can also engage in competitive interactions with transcriptional regulators such as GATA1 to promote myeloid differentiation ( Strasser et al, 2018 ; Wheat et al, 2020 ; Raghav and Gangenahalli, 2021 ). Thus, reduced PU.1 expression in PU.1 KI/KI HSPC likely initiates a ‘ripple effect’ that disrupts additional transcriptional networks controlling the balance between myeloid differentiation and self-renewal.…”

Section: Discussionmentioning

confidence: 99%

PU.1 is required to restrain myelopoiesis during chronic inflammatory stress

Rabe

Niño

Wells

et al. 2023

Front. Cell Dev. Biol.

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Chronic inflammation is a common feature of aging and numerous diseases such as diabetes, obesity, and autoimmune syndromes and has been linked to the development of hematological malignancy. Blood-forming hematopoietic stem cells (HSC) can contribute to these diseases via the production of tissue-damaging myeloid cells and/or the acquisition of mutations in epigenetic and transcriptional regulators that initiate evolution toward leukemogenesis. We previously showed that the myeloid “master regulator” transcription factor PU.1 is robustly induced in HSC by pro-inflammatory cytokines such as interleukin (IL)-1β and limits their proliferative activity. Here, we used a PU.1-deficient mouse model to investigate the broader role of PU.1 in regulating hematopoietic activity in response to chronic inflammatory challenges. We found that PU.1 is critical in restraining inflammatory myelopoiesis via suppression of cell cycle and self-renewal gene programs in myeloid-biased multipotent progenitor (MPP) cells. Our data show that while PU.1 functions as a key driver of myeloid differentiation, it plays an equally critical role in tailoring hematopoietic responses to inflammatory stimuli while limiting expansion and self-renewal gene expression in MPPs. These data identify PU.1 as a key regulator of “emergency” myelopoiesis relevant to inflammatory disease and leukemogenesis.

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Section: Discussionmentioning

confidence: 99%

PU.1 is required to restrain myelopoiesis during chronic inflammatory stress

Rabe

Niño

Wells

et al. 2023

Front. Cell Dev. Biol.

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“…It causes a maturation arrest in the transition of HSCs to CLP and CMP phenotypes, hence establishing PU.1 requirement for the competitive self-renewal of HSCs. However, a low level of PU.1 expression is required for HSCs maintenance, whereas an increased level causes myeloid differentiation ( Iwasaki et al, 2005 ; Raghav and Gangenahalli, 2021 ). The exact mechanism of PU.1 is still under speculation; however, a recent study reported the role of non-canonical Wnt signaling in HSCs self-renewal and myeloid lineage differentiation ( Welner et al, 2020 ).…”

Section: Factors For Hematopoietic Stem Cells Stemness and Self-renewalmentioning

confidence: 99%

Hematopoietic Stem Cell Factors: Their Functional Role in Self-Renewal and Clinical Aspects

Mann¹,

Sengar

Verma

et al. 2022

Front. Cell Dev. Biol.

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Hematopoietic stem cells (HSCs) possess two important properties such as self-renewal and differentiation. These properties of HSCs are maintained through hematopoiesis. This process gives rise to two subpopulations, long-term and short-term HSCs, which have become a popular convention for treating various hematological disorders. The clinical application of HSCs is bone marrow transplant in patients with aplastic anemia, congenital neutropenia, sickle cell anemia, thalassemia, or replacement of damaged bone marrow in case of chemotherapy. The self-renewal attribute of HSCs ensures long-term hematopoiesis post-transplantation. However, HSCs need to be infused in large numbers to reach their target site and meet the demands since they lose their self-renewal capacity after a few passages. Therefore, a more in-depth understanding of ex vivo HSCs expansion needs to be developed to delineate ways to enhance the self-renewability of isolated HSCs. The multifaceted self-renewal process is regulated by factors, including transcription factors, miRNAs, and the bone marrow niche. A developed classical hierarchical model that outlines the hematopoiesis in a lineage-specific manner through in vivo fate mapping, barcoding, and determination of self-renewal regulatory factors are still to be explored in more detail. Thus, an in-depth study of the self-renewal property of HSCs is essentially required to be utilized for ex vivo expansion. This review primarily focuses on the Hematopoietic stem cell self-renewal pathway and evaluates the regulatory molecular factors involved in considering a targeted clinical approach in numerous malignancies and outlining gaps in the current knowledge.

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Exploring the contribution of Zfp521/ZNF521 on primary hematopoietic stem/progenitor cells and leukemia progression

Chiarella

2024

Cell Tissue Res

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Hematopoietic stem cells (HSCs) drive cellular turnover in the hematopoietic system by balancing self-renewal and differentiation. In the adult bone marrow (BM), these cells are regulated by a complex cellular microenvironment known as “niche,” which involves dynamic interactions between diverse cellular and non-cellular elements. During blood cell maturation, lineage branching is guided by clusters of genes that interact or counteract each other, forming complex networks of lineage-specific transcription factors. Disruptions in these networks can lead to obstacles in differentiation, lineage reprogramming, and ultimately malignant transformation, including acute myeloid leukemia (AML). Zinc Finger Protein 521 (Znf521/Zfp521), a conserved transcription factor enriched in HSCs in both human and murine hematopoiesis, plays a pivotal role in regulating HSC self-renewal and differentiation. Its enforced expression preserves progenitor cell activity, while inhibition promotes differentiation toward the lymphoid and myeloid lineages. Transcriptomic analysis of human AML patient samples has revealed upregulation of ZNF521 in AMLs with the t(9;11) fusion gene MLL-AF9. In vitro studies have shown that ZNF521 collaborates with MLL-AF9 to enhance the growth of transformed leukemic cells, increase colony formation, and activate MLL target genes. Conversely, inhibition of ZNF521 using short-hairpin RNA (shRNA) results in decreased leukemia proliferation, reduced colony formation, and induction of cell cycle arrest in MLL-rearranged AML cell lines. In vivo experiments have demonstrated that mZFP521-deficient mice transduced with MLL-AF9 experience a delay in leukemia development. This review provides an overview of the regulatory network involving ZNF521, which plays a crucial role in controlling both HSC self-renewal and differentiation pathways. Furthermore, we examine the impact of ZNF521 on the leukemic phenotype and consider it a potential marker for MLL-AF9 + AML.

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PU.1 Mimic Synthetic Peptides Selectively Bind with GATA-1 and Allow c-Jun PU.1 Binding to Enhance Myelopoiesis

Cited by 10 publications

References 61 publications

PU.1 is required to restrain myelopoiesis during chronic inflammatory stress

PU.1 is required to restrain myelopoiesis during chronic inflammatory stress

Hematopoietic Stem Cell Factors: Their Functional Role in Self-Renewal and Clinical Aspects

Exploring the contribution of Zfp521/ZNF521 on primary hematopoietic stem/progenitor cells and leukemia progression

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