The Role of PU.1 and Spi-B in B Cell Acute Lymphoblastic Leukemia

ETV6-RUNX1 is the most common chromosomal alteration in pediatric B cell acute lymphoblastic leukemia. ETV6-RUNX1 represses RUNX1 target genes. However, little is known about the target genes of ETV6-RUNX1 that are involved in promoting leukemogenesis. A recent study with two human leukemia cell lines AT-2 and REH, which express ETV6-RUNX1, suggested that SPIB was one of the top of the genes that were up regulated after knocking down the ETV6-RUNX1 fusion protein. In addition, our lab showed that deletion of PU.1 and Spi-B in B cells in mice resulted in the development of B cell acute lymphoblastic leukemia with 100% incidence. It is still not clear what pathways and target genes are affected by the loss of PU.1 and Spi-B and contribute to leukemogenesis. We hypothesized that ETV6-RUNX1 function as an oncogenic driver by repressing SPIB transcription, leading to impaired B cell receptor signaling. This hypothesis was divided into two parts. First, examining how PU.1 and Spi-B could act as tumor suppressor genes in B cells in our mouse model using gene expression profiling. The results of the microarray specified impairment in the expression of genes involved in BCR signaling pathways. Second, we aimed to determine the molecular mechanism of how SPIB is repressed by ETV6-RUNX1. ChIP results suggested that ETV6-RUNX1 directly interacts with SPIB. This study is expected to lead to a deeper understanding of the underlying biology of leukemogenesis caused by the loss of SPIB in ETV6-RUNX1 leukemia patients, hence allowing for the development of new molecular targeted therapies for B-cell leukemi

PU.1 opposes IL-7-dependent proliferation of developing b cells with involvement of the direct target gene bruton tyrosine kinase

Deletion of genes encoding the E26 transformation-specific transcription factors PU.1 and Spi-B in B cells (CD19-CreΔPB mice) leads to impaired B cell development, followed by B cell acute lymphoblastic leukemia at 100% incidence and with a median survival of 21 wk. However, little is known about the target genes that explain leukemogenesis in these mice. In this study we found that immature B cells were altered in frequency in the bone marrow of preleukemic CD19-CreΔPB mice. Enriched pro-B cells from CD19-CreDPB mice induced disease upon transplantation, suggesting that these were leukemia-initiating cells. Bone marrow cells from preleukemic CD19-CreΔPB mice had increased responsiveness to IL-7 and could proliferate indefinitely in response to this cytokine. Bruton tyrosine kinase (BTK), a negative regulator of IL-7 signaling, was reduced in preleukemic and leukemic CD19-CreΔPB cells compared with controls. Induction of PU.1 expression in cultured CD19-CreΔPB pro-B cell lines induced Btk expression, followed by reduced STAT5 phosphorylation and early apoptosis. PU.1 and Spi-B regulated Btk directly as shown by chromatin immunoprecipitation analysis. Ectopic expression of BTK was sufficient to induce apoptosis in cultured pro-B cells. In summary, these results suggest that PU.1 and Spi-B activate Btk to oppose IL-7 responsiveness in developing B cells

PU.1 opposes IL-7-dependent proliferation of developing b cells with involvement of the direct target gene bruton tyrosine kinase

Deletion of genes encoding the E26 transformation-specific transcription factors PU.1 and Spi-B in B cells (CD19-CreΔPB mice) leads to impaired B cell development, followed by B cell acute lymphoblastic leukemia at 100% incidence and with a median survival of 21 wk. However, little is known about the target genes that explain leukemogenesis in these mice. In this study we found that immature B cells were altered in frequency in the bone marrow of preleukemic CD19-CreΔPB mice. Enriched pro-B cells from CD19-CreDPB mice induced disease upon transplantation, suggesting that these were leukemia-initiating cells. Bone marrow cells from preleukemic CD19-CreΔPB mice had increased responsiveness to IL-7 and could proliferate indefinitely in response to this cytokine. Bruton tyrosine kinase (BTK), a negative regulator of IL-7 signaling, was reduced in preleukemic and leukemic CD19-CreΔPB cells compared with controls. Induction of PU.1 expression in cultured CD19-CreΔPB pro-B cell lines induced Btk expression, followed by reduced STAT5 phosphorylation and early apoptosis. PU.1 and Spi-B regulated Btk directly as shown by chromatin immunoprecipitation analysis. Ectopic expression of BTK was sufficient to induce apoptosis in cultured pro-B cells. In summary, these results suggest that PU.1 and Spi-B activate Btk to oppose IL-7 responsiveness in developing B cells

The miR-155-PU.1 axis acts on Pax5 to enable efficient terminal B cell differentiation.

A single microRNA (miRNA) can regulate the expression of many genes, though the level of repression imparted on any given target is generally low. How then is the selective pressure for a single miRNA/target interaction maintained across long evolutionary distances? We addressed this problem by disrupting in vivo the interaction between miR-155 and PU.1 in mice. Remarkably, this interaction proved to be key to promoting optimal T cell-dependent B cell responses, a previously unrecognized role for PU.1. Mechanistically, miR-155 inhibits PU.1 expression, leading to Pax5 down-regulation and the initiation of the plasma cell differentiation pathway. Additional PU.1 targets include a network of genes whose products are involved in adhesion, with direct links to B-T cell interactions. We conclude that the evolutionary adaptive selection of the miR-155-PU.1 interaction is exercised through the effectiveness of terminal B cell differentiation

A critical Hadith study of the Tablighi Nisab and its intellectual impact on the Jama at Al-Tabligh.

It is common knowledge that movements are based on ideologies that are considered to be the foundation of their methodologies and policies. Often, these ideologies are disseminated in letters, books or other publications that present them in the form of texts that are available to the public and become sources of information about these movements. The Jamā‘at Al-Tablīgh is one of the movements that plays an important role in the sphere of Islamic Da‘wah (mission). This movement adopts some techniques of Da‘wah; one of the most important among them being Targhīb, which expounds the merits and benefits of virtuous deeds. This research studies one of the most popular books of the movement, titled in Urdu Tablīghī Nisāb, which uses this sort of technique. It was written by the famous H adīth scholar and the general supervisor of the movement, Shaykh Muhammad Zakariyyā Kāndahlawī. The first publication of the book in Urdu was in (1374 H./1955 CE.). It has been translated into several different languages, and this reflects the importance of the book. The thesis falls into six chapters, including the introduction as chapter one and the conclusion as chapter six. Chapter two talks about the definition of weak Ahadīth and its different types, criteria used to determine weak Ahādīth, different trends among the scholars regarding weak Ahādīth, the consequences of using and publicizing weak and fabricated Ahādīth. Chapter three deals with the biography of the author of the Tablīghī Nisāb, while chapter four focuses on the book itself, by specifying the original name of it and looking at the different editions and translations, and compares the original Urdu with the Arabic and English versions. The chapter also discusses the methodology of the author in his book. Chapter five is a critical study of the Ahādīth of the Tablīghī Nisāb, whether found in the main text of the book or in the commentary to verify the Ahādīth in terms of their authenticity or weakness

Adaptive wireless thin-client model for mobile computing

The thin-client computing model has the potential to significantly increase the performance of mobile computing environments. By delivering any application through a single, small-footprint client (called a thin client) implemented on a mobile device, it is possible to optimize application performance without the need for building wireless application gateways. We thus present two significant contributions in the area of wireless thin-client computing. Firstly, a mathematical performance model is derived for wireless thin-client system. This model identifies factors that affect the performance of the system and supports derivation and analysis of adaptation strategies to maintain a user-specified quality of service (QoS). Secondly, a proxy-based adaptation framework is developed for wireless thin-client systems, which dynamically optimizes performance of a wireless thin client via dynamically discovered context. This is implemented with rule-based fuzzy logic that responds to variations in wireless link bandwidth and client processing power. Our fuzzy inference engine uses contextual data to dynamically optimize tradeoffs among different quality of service parameters offered to the end users. Additionally, our adaptation framework uses highly scalable wavelet-based image coding to provide scalable QoS that can degrade gracefully. Our thin-client adaptation framework shields the user from ill effects of highly variable wireless network quality and mobile device resources. This improves performance of active applications, in which the display changes frequently. Further, active application behaviour may produce high transmission latency for screen updates, which can adversely affect user perception of QoS, resulting in poor interactivity. We report measured adaptive performance under realistic mobile device and network conditions for several different clients and servers. Copyright © 2008 John Wiley & Sons, Ltd