Publications by authors named "Shih-Shih Chen"

Deuterated ("heavy") water labeling in patients with chronic lymphocytic leukemia (CLL) demonstrates that IGHV unmutated and ZAP-70+ patients have higher blood and tissue CLL death rates on ibrutinib therapy, resulting in lower measurable residual disease levels with long-term ibrutinib treatment. This trial was registered at www.clinicaltrials.

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The development and progression of chronic lymphocytic leukemia (CLL) depend on genetic abnormalities and on the immunosuppressive microenvironment. We have explored the possibility that genetic drivers might be responsible for the immune cell dysregulation that shapes the protumor microenvironment. We performed a transcriptome analysis of coding and non-coding RNAs (ncRNAs) during leukemia progression in the Rag2γ MEC1-based xenotransplantation model.

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Article Synopsis
  • The treatment landscape for chronic lymphocytic leukemia (CLL) is evolving, yet there are still significant unmet needs as many patients face issues with resistance, relapses, or transformation into a more aggressive form known as Richter transformation (RT).
  • RT is particularly challenging due to its association with diffuse large B-cell lymphoma (DLBCL) and limited treatment options, compounded by immune dysfunction in CLL patients, where the tumor microenvironment fosters immunosuppressive cells.
  • The review emphasizes the importance of understanding CLL and RT biology through advanced mouse models to explore disease progression and potential innovative therapies aimed at effectively treating these cancers.
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  • - Chronic lymphocytic leukemia (CLL) is a complex disease involving the growth of specific B cells in lymphoid tissues, with existing treatments showing benefits but still leaving room for improvement, particularly for relapsing patients.
  • - Patients often face challenges like relapses and severe complications such as Richter transformation, highlighting the need for better immunotherapies and predictive biomarkers for treatment strategies.
  • - The review discusses the use of CRISPR-engineered and xenograft mouse models that mimic human CLL, allowing researchers to explore disease mechanisms and the role of specific mutations in progression, while also considering the potential of next-generation humanized mice for more accurate studies.
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  • The study explores targeting tumor-specific mutations in cancer through precision cell therapy, focusing on B cell receptors (BCR) that have unique mutations in chronic lymphocytic leukemia (CLL).
  • Researchers developed chimeric antigen receptor (CAR) T cells that specifically target a neoepitope defined by a notable mutation (IGLV3-21), successfully eradicating cancer cells without harming healthy B cells.
  • In vivo experiments using mouse models confirmed that the CAR T cells selectively destroy malignant cells expressing the IGLV3-21 mutation while safeguarding normal B cells, suggesting a promising approach for treating CLL.
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  • Chronic lymphocytic leukemia (CLL) B cells depend on interactions with non-malignant cells and the tissue environment for survival and growth, mediated by specific receptors like BCR and CXCR4.
  • Activation of these receptors triggers Bruton's tyrosine kinase (BTK), which helps prevent cell death and promotes growth, allowing cells to receive supportive signals.
  • Ibrutinib, a BTK inhibitor, effectively helps patients with CLL and some lymphomas by blocking these supportive signals rather than causing cell death.
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Purpose: Inhibitors of Bruton's tyrosine kinase (BTKi) and PI3K (PI3Ki) have significantly improved therapy of chronic lymphocytic leukemia (CLL). However, the emergence of resistance to BTKi has introduced an unmet therapeutic need. Hence, we sought evidence for essential roles of PI3K-δi and PI3K-γi in treatment-naïve and BTKi-refractory CLL.

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Cancer pathogenesis involves the interplay of tumor- and microenvironment-derived stimuli. Here we focused on the influence of an immunomodulatory cell type, myeloid-derived suppressor cells (MDSCs), and their lineage-related subtypes on autologous T lymphocytes. Although MDSCs as a group correlated with an immunosuppressive Th repertoire and worse clinical course, MDSC subtypes (polymorphonuclear, PMN-MDSC, and monocytic, M-MDSCs) were often functionally discordant.

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Patient-derived xenograft models of chronic lymphocytic leukemia (CLL) can be created using highly immunodeficient animals, allowing analysis of primary tumor cells in an setting. However, unlike many other tumors, CLL B lymphocytes do not reproducibly grow in xenografts without manipulation, proliferating only when there is concomitant expansion of T cells. Here we show that pre-activation of CLL-derived T lymphocytes allows for a reliable and robust system for primary CLL cell growth within a fully autologous system that uses small numbers of cells and does not require pre-conditioning.

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Progression of chronic lymphocytic leukemia (CLL) results from the expansion of a small fraction of proliferating leukemic B cells. When comparing the global gene expression of recently divided CLL cells with that of previously divided cells, we found higher levels of genes involved in regulating gene expression. One of these was the oncogene Musashi 2 (MSI2), an RNA-binding protein that induces or represses translation.

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The chemoattractant CXCL13 organizes the cellular architecture of B-cell follicles and germinal centers. During adaptive immune responses, CXCL13 plasma concentrations transiently increase and function as a biomarker for normal germinal center activity. Chronic lymphocytic leukemia (CLL) cells express high levels of CXCR5, the receptor for CXCL13, and proliferate in pseudofollicles within secondary lymphoid organs (SLO).

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Article Synopsis
  • Chronic lymphocytic leukemia (CLL) patients are categorized into three groups based on disease severity: minimal impact (no therapy), initial indolence (progressing to therapy), and aggressive cases (immediate treatment needed).
  • The disease follows a timeline including development, diagnosis, and therapeutic intervention, influenced by external factors from the tissue microenvironment and internal genetic changes.
  • Key focus areas include the role of B-cell receptors in cell survival and therapeutic agents that target these interactions, as well as inherited susceptibility genes and genetic/epigenetic alterations linked to the disease's progression.
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  • The tumor microenvironment in leukemia and solid tumors forces activated CD8 T cells into an exhausted state, which hampers their ability to proliferate and form effective immune responses.
  • Research using mouse models for chronic lymphocytic leukemia (CLL) and melanoma showed that the SLAMF6 receptor plays a key role in regulating these exhausted T cells, as its presence led to an expansion of dysfunctional T-cell populations.
  • Administering anti-SLAMF6 treatment not only reduced tumor burden in leukemia models but also improved T-cell functionality, indicating that targeting SLAMF6 could be a promising therapeutic approach for various cancers.
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Targeted therapy is revolutionizing the treatment of cancers, but resistance evolves against these therapies and derogates their success. The phosphatidylinositol 3-kinase delta (PI3K-δ) inhibitor idelalisib has been approved for treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma, but the mechanisms conferring resistance in a subset of patients are unknown. Here, we modeled resistance to PI3K-δ inhibitor in vivo using a serial tumor transfer and treatment scheme in mice.

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Richter syndrome is the name given to the transformation of the most frequent type of leukemia, chronic lymphocytic leukemia, into an aggressive lymphoma. Patients with Richter syndrome have limited response to therapies and dismal survival. The underlying mechanisms of transformation are insufficiently understood and there is a major lack of knowledge regarding the roles of microRNA that have already proven to be causative for most cases of chronic lymphocytic leukemia.

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Patient-derived xenograft (PDX) models are created by implantation of tumor cells into immunodeficient mice. These models maintain similar morphology and molecular profiling of the original tumors, and therefore have been extensively used in cancer research in both the basic and preclinical fields. Here, we describe a PDX model of CLL using autologous activated T cells to support CLL B-cell growth in lymphoid tissues such as spleen and bone marrow.

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Bispecific antibodies (biAb) targeting two different antigens or two distinct epitopes on the same antigen have demonstrated broad therapeutic utility. CD52 and CD20 are co-expressed on the cell surface of malignant B cells in B-cell non-Hodgkin lymphoma (B-NHL) and chronic lymphocytic leukemia (CLL) and increased expression of both antigens is detected on dividing or recently divided cells ("proliferative fraction") in CLL. The CD52-targeting monoclonal antibody (mAb) alemtuzumab (atz) not only depletes malignant B cells but also healthy CD52 B and T lymphocytes and monocytes, causing severe immunosuppression.

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Targeting the B-cell receptor (BCR) pathway with inhibitors of Bruton tyrosine kinase (BTK) and PI3Kδ is highly effective for the treatment of chronic lymphocytic leukemia (CLL). However, deep remissions are uncommon, and drug resistance with single-agent therapy can occur. studies support the effectiveness of combing PI3Kδ and BTK inhibitors.

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Article Synopsis
  • Ibrutinib is a targeted therapy for chronic lymphocytic leukemia (CLL) that works by inhibiting Bruton's tyrosine kinase (BTK), which is critical in B cell signaling.
  • The study involved 30 CLL patients and found that before treatment, the average proliferation rate of leukemia cells was 0.39% per day, which dropped significantly to 0.05% after starting ibrutinib.
  • Furthermore, the death rate of CLL cells increased dramatically from 0.18% per day to 1.5% during treatment, indicating that ibrutinib not only slows down cell growth but also boosts cell death rates.
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Chronic lymphocytic leukemia (CLL) is a progressive malignancy of mature B-cells that involves the peripheral blood (PB), lymph nodes (LNs) and bone marrow (BM). Although the majority of CLL cells are in a resting state, small populations of proliferating cells exist; however, the anatomical site of active cell proliferation remains to be definitively determined. Based on findings that CLL cells in LNs have increased expression of B-cell activation genes, we tested the hypothesis that the fraction of 'newly born' cells would be highest in the LNs.

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The chronic lymphocytic leukemia (CLL) niche is a closed environment where leukemic cells derive growth and survival signals through their interaction with macrophages and T lymphocytes. Here, we show that the CLL lymph node niche is characterized by overexpression and activation of HIF-1α, which increases adenosine generation and signaling, affecting tumor and host cellular responses. Hypoxia in CLL lymphocytes modifies central metabolic pathways, protects against drug-driven apoptosis, and induces interleukin 10 (IL-10) production.

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Article Synopsis
  • - Xenografting primary chronic lymphocytic leukemia (CLL) B lymphocytes with activated T cells into alymphoid mice leads to significant B cell division and T cell expansion, but most CLL B cells eventually get lost as they differentiate into antibody-secreting cells.
  • - The differentiation of CLL B cells involves changes like isotype class switching and mutations, facilitated by T-bet T cells instead of traditional T follicular helper cells, and involves pathways dependent on activation-induced deaminase.
  • - Key characteristics of CLL, such as impaired B cell maturation and reduced T cell function, are attributed to external signals from the microenvironment rather than being innate to the cancer cells themselves, suggesting that CLL cell
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The signaling lymphocyte activation molecule family [SLAMF] of cell surface receptors partakes in both the development of several immunocyte lineages and innate and adaptive immune responses in humans and mice. For instance, the homophilic molecule SLAMF6 (CD352) is in part involved in natural killer T cell development, but also modulates T follicular helper cell and germinal B cell interactions. Here we report that upon transplantation of a well-defined aggressive murine B220+CD5+ Chronic Lymphocytic Leukemia (CLL) cell clone, TCL1-192, into SCID mice one injection of a monoclonal antibody directed against SLAMF6 (αSlamf6) abrogates tumor progression in the spleen, bone marrow and blood.

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Article Synopsis
  • *Genetic abnormalities in both hematopoietic stem cells and B lymphocytes contribute to the disease, with further changes occurring over time that can worsen patient outcomes.
  • *To better understand CLL and improve treatments, developing genetically engineered mouse models is crucial, although diverse models may be needed to account for the genetic variability seen in different patients.
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