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CLL Humans

Dorina Ujvari, Noemi Nagy, Harsha S Madapura, Tomasz Kallas, Marijke C L Kröhnke, Leif Stenke, Eva Klein, Daniel Salamon
B-cell CLL/lymphoma 6 (BCL6) is a transcriptional master regulator that can repress more than 1200 potential target genes. It exerts oncogenic effects through the inhibition of differentiation, DNA damage sensing and apoptosis in several human hematopoietic malignancies, including multiple myeloma (MM). The multifunctional cytokine interferon γ (IFNγ) exerts pro-apoptotic and anti-proliferative effects on MM cells in vitro, at least partially through the inhibition of the effects of interleukin 6 (IL6), one of the most important growth factor of MM and a strong inducer of BCL6 expression...
March 3, 2018: Biochemical and Biophysical Research Communications
Ailsa K Holroyd, Alison M Michie
Mechanistic target for rapamycin (mTOR) is a serine/threonine protein kinase that forms two distinct complexes mTORC1 and mTORC2, integrating mitogen and nutrient signals to regulate cell survival and proliferation; processes which are commonly deregulated in human cancers. mTORC1 and mTORC2 have divergent molecular associations and cellular functions: mTORC1 regulates in mRNA translation and protein synthesis, while mTORC2 is involved in the regulation of cellular survival and metabolism. Through AKT phosphorylation/activation, mTORC2 has also been reported to regulate cell migration...
February 3, 2018: Immunology Letters
Yue Gu, Aifang Li, Hui Sun, Xueru Li, He Zha, Jiali Zhao, Jiaqing Xie, Zongyue Zeng, Lan Zhou
B‑cell CLL/lymphoma 6 member B (BCL6B), a BCL6‑homologous gene, has been reported to be a tumor suppressor that is silenced in a variety of human cancers, including colorectal cancer (CRC). Although it was recently demonstrated that reduced expression of BCL6B is associated with tumor stage and lymph node metastasis in CRC, little is known on whether BCL6B contributes to CRC development, or the related underlying mechanism. The aim of the present study was to detect BCL6B expression in CRC cells, and determine the molecular mechanisms underlying the role of BCL6B in CRC development by investigating cell proliferation and migration in vitro...
February 1, 2018: International Journal of Molecular Medicine
Emily D Rout, Robert C Burnett, Julia D Labadie, Janna A Yoshimoto, Anne C Avery
Human chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease, and immunoglobulin heavy variable region (IGHV) gene mutational status is an important prognostic marker. IGHV mutational status has not been previously examined in canine CLL. We sequenced the IGHV-D-J rearrangements from 55 canine patients with CLL, including 36 non-Boxer and 19 Boxer dogs. The majority of non-Boxers (75%) had mutated IGHV genes, whereas the majority of Boxers (79%) had unmutated IGHV genes. IGHV3-41 and IGHV3-67 gene usage was significantly higher in Boxers with CLL compared to non-Boxers...
2018: PloS One
Tianxiang Hu, Yating Chong, Haiyan Qin, Eiko Kitamura, Chang-Sheng Chang, Jeane Silva, Mingqiang Ren, John K Cowell
MicroRNAs (miRNAs) have pathogenic roles in the development of a variety of leukemias. Here we identify miRNAs that have important roles in the development of B lymphomas resulting from the expression of the chimeric BCR-FGFR1 kinase. The miR-17/92 cluster was particularly implicated and forced expression resulted in increased cell proliferation, while inhibiting its function using miRNA sponges reduced cell growth and induced apoptosis. Cells treated with the potent BGJ389 FGFR1 inhibitor led to miR-17/92 downregulation, suggesting regulation by FGFR1...
January 25, 2018: Oncogene
Fang Zhu, Lindsay McCaw, David E Spaner, Reginald M Gorczynski
The tumor microenvironment (TME) is critical to the longevity of tumor B cells in chronic lymphocytic leukemia (CLL). Bone marrow mesenchymal stem cells (BMMSCs) and the cytokines they produce including IL-6 are important components of the TME in CLL. We found BMMSCs supported the survival of CLL cells in vitro through an IL-6 dependent mechanism. IL-17 which induces IL-6 generation in a variety of cells increased production of IL-6 both in CLL cells and BMMSCs in vitro. In a xenograft CLL mouse model, BMMSCs and the culture supernatant of BMMSCs increased engraftment of CLL cells through an IL-6 mediated mechanism with human recombinant IL-6 showing similar effects in vivo...
January 17, 2018: Leukemia Research
Julia C Gutjahr, Eva Szenes, Lisa Tschech, Daniela Asslaber, Michaela Schlederer, Simone Roos, Xiaobing Yu, Tamara Girbl, Christina Sternberg, Alexander Egle, Fritz Aberger, Ronen Alon, Lukas Kenner, Richard Greil, Veronique Orian-Rousseau, Tanja N Hartmann
Chronic lymphocytic leukemia (CLL) outgrowth depends on signals from the microenvironment. We have previously found that in vitro reconstitution of this microenvironment induces specific variant isoforms of the adhesion molecule CD44, which confer human CLL with high affinity to hyaluronan (HA). Here, we determined the in vivo contribution of standard CD44 and its variants to leukemic B-cell homing and proliferation in Tcl1 transgenic mice with a B-cell-specific CD44 deficiency. In these mice, leukemia onset was delayed and leukemic infiltration of spleen, liver, and lungs, but not of bone marrow was decreased...
January 19, 2018: Blood
Pavlina Janovska, Jan Verner, Jiri Kohoutek, Lenka Bryjova, Michaela Gregorova, Marta Dzimkova, Hana Skabrahova, Tomasz Radaszkiewicz, Petra Ovesna, Olga Vondalova Blanarova, Tereza Nemcova, Zuzana Hoferova, Katerina Vasickova, Lucie Smyckova, Alexander Egle, Sarka Pavlova, Lucie Poppova, Karla Plevova, Sarka Pospisilova, Vitezslav Bryja
Casein kinase (CK) 1δ/ε is a key component of non-canonical Wnt signaling pathways, which were shown previously to drive pathogenesis of chronic lymphocytic leukemia (CLL). In this study we investigated thoroughly the effects of CK1δ/ε inhibition on the primary CLL cells and analyzed the therapeutic potential in vivo using two murine model systems based on the Eµ-TCL1-induced leukemia (syngeneic adoptive transfer model and spontaneous disease development), which resemble closely the human CLL. We can demonstrate that CK1δ/ε inhibitor PF-670462 significantly blocks microenvironmental interactions - chemotaxis, invasion and communication with stromal cells in primary CLL cells in all major subtypes of CLL...
January 9, 2018: Blood
Jinghua Wang, Siyu Chen, Wei Xiao, Wende Li, Liang Wang, Shuo Yang, Weida Wang, Liping Xu, Shuangye Liao, Wenjian Liu, Yang Wang, Nawei Liu, Jianeng Zhang, Xiaojun Xia, Tiebang Kang, Gong Chen, Xiuyu Cai, Han Yang, Xing Zhang, Yue Lu, Penghui Zhou
BACKGROUND: Acute myeloid leukemia (AML) is one of the most common types of adult acute leukemia. Standard chemotherapies can induce complete remission in selected patients; however, a majority of patients eventually relapse and succumb to the disease. Thus, the development of novel therapeutics for AML is urgently needed. Human C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein, and its expression is restricted to myeloid cells and the majority of AML blasts...
January 10, 2018: Journal of Hematology & Oncology
Gordon T Bolger, Albert Licollari, Aimin Tan, Richard Greil, Lisa Pleyer, Brigitta Vcelar, Muhammad Majeed, Peter Sordillo
Background/Aim: Curcumin is being widely investigated for its anticancer properties and studies in the literature suggest that curcumin distributes to a higher degree in tumor versus non-tumor cells. In the current study, we report on investigation of the distribution of curcumin and metabolism to THC in PBMC from healthy individuals and chronic lymphocytic leukemia (CLL) patients following exposure to Lipocurc™ (liposomal curcumin). Materials and Methods: The time and temperature-dependent distribution of liposomal curcumin and metabolism to tetrahydrocurcumin (THC) were measured in vitro in human peripheral blood mononuclear cells (PBMC) obtained from healthy individuals, PBMC HI (cryopreserved and freshly isolated PBMC) and CLL patients (cryopreserved PBMC) with lymphocyte counts ranging from 17-58×10 6 cells/ml (PBMC CLL,Grp 1 ) and >150×10 6 cells/ml (PBMC CLL,Grp 2 )...
January 2018: Anticancer Research
Rupert L Mayer, Josef D Schwarzmeier, Marlene C Gerner, Andrea Bileck, Johanna C Mader, Samuel M Meier-Menches, Samuel M Gerner, Klaus G Schmetterer, Tobias Pukrop, Albrecht Reichle, Astrid Slany, Christopher Gerner
B cell chronic lymphocytic leukemia (B-CLL), the most common type of leukemia in adults, is still essentially incurable despite the development of novel therapeutic strategies. This reflects the incomplete understanding of the pathophysiology of this disease. A comprehensive proteome analysis of primary human B-CLL cells and B cells from younger as well as elderly healthy donors was performed. For comparison, the chronic B cell leukemia cell line JVM-13 was also included. A principal component analysis comprising 6,945 proteins separated these four groups, placing B cells of aged-matched controls between those of young donors and B-CLL patients, while identifying JVM-13 as poorly related cells...
February 2018: Molecular & Cellular Proteomics: MCP
Avinash Gothwal, Iliyas Khan, Pramod Kumar, Kaisar Raza, Ankur Kaul, Anil Kumar Mishra, Umesh Gupta
Successful delivery of chemotherapeutic agent like bendamustine still remains a challenge in the clinical conditions like Chronic lymphatic leukemia (CLL), Non-Hodgkin lymphoma (NHL) and multiple myeloma. We have conjugated bendamustine to Polyamidoamine (PAMAM) dendrimers after conjugating with N-hydroxyethylmaleimide (spacer) via an ester bond. The particle size of PAMAM-bendamustine conjugate was 49.8±2.5 nm. In vitro drug release resulted in sustained release with improved solution stability of drug up to 72 h...
December 1, 2017: Molecular Pharmaceutics
Sara Sandri, Francesco De Sanctis, Alessia Lamolinara, Federico Boschi, Ornella Poffe, Rosalinda Trovato, Alessandra Fiore, Sara Sartori, Andrea Sbarbati, Attilio Bondanza, Simone Cesaro, Mauro Krampera, Maria T Scupoli, Michael I Nishimura, Manuela Iezzi, Silvia Sartoris, Vincenzo Bronte, Stefano Ugel
Telomerase (TERT) is a ribonucleoprotein enzyme that preserves the molecular organization at the ends of eukaryotic chromosomes. Since TERT deregulation is a common step in leukaemia, treatments targeting telomerase might be useful for the therapy of hematologic malignancies. Despite a large spectrum of potential drugs, their bench-to-bedside translation is quite limited, with only a therapeutic vaccine in the clinic and a telomerase inhibitor at late stage of preclinical validation. We recently demonstrated that the adoptive transfer of T cell transduced with an HLA-A2-restricted T-cell receptor (TCR), which recognize human TERT with high avidity, controls human B-cell chronic lymphocytic leukaemia (B-CLL) progression without severe side-effects in humanized mice...
October 20, 2017: Oncotarget
Jaime Stella Moses Richardson, Norhaniza Aminudin, Sri Nurestri Abd Malek
Background: Plants have been a major source of inspiration in developing novel drug compounds in the treatment of various diseases that afflict human beings worldwide. Ruta angustifolia L. Pers known locally as Garuda has been conventionally used for various medicinal purposes such as in the treatment of cancer. Objective: A dihydrofuranocoumarin named chalepin, which was isolated from the chloroform extract of the plant, was tested on its ability to inhibit molecular pathways of human lung carcinoma (A549) cells...
October 2017: Pharmacognosy Magazine
Thomas M Cardillo, Serengulam V Govindan, Maria B Zalath, Diane L Rossi, Yang Wang, Chien-Hsing Chang, David M Goldenberg
HLA-DR is a member of the MHC class II antigen family expressed on hematological and solid tumors.  Antibodies directed against HLA-DR have demonstrated some clinical success, but toxicities limited development.  IMMU-140 is an anti-HLA-DR antibody-drug conjugate comprised of the active metabolite of irinotecan, SN-38, conjugated to a humanized anti-HLA-DR IgG4 antibody (IMMU-114); the IgG4 naked antibody is devoid of immune functions. Our aim was to determine if SN-38, the metabolite of a drug not commonly used in hematopoietic cancers, would be effective and safe when targeted to HLA-DR-expressing tumors...
November 13, 2017: Molecular Cancer Therapeutics
Fei Xie, Lei Yang, Lili Han, Bin Yue
The present study explored the functional role of microRNA (miR)-194 in lipopolysaccharide (LPS) induced lung cell injury, along with the underlying mechanisms and to reveal the potential role in infantile pneumonia. Human fibroblasts WI38 cells were transfected with miR-194 mimic or miR-194 inhibitor, and the transfection efficiency was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). Thereafter, the cells were treated with or without LPS, and then cell viability, cell apoptosis and mRNA and protein expressions of key proteins of nuclear factor kappa B (NF-κB) pathway including inhibitor of NF-κB (IκB) α, p-65, and B-cell CLL/lymphoma (Bcl) 3 were analyzed...
October 31, 2017: Cellular Physiology and Biochemistry
Aleena A Gladkikh, Daria M Potashnikova, Victor Tatarskiy, Margarita Yastrebova, Alvina Khamidullina, Natasha Barteneva, Ivan Vorobjev
The B-cell receptor (BCR) signaling pathway is of great importance for B-cell survival and proliferation. The BCR expressed on malignant B-CLL cells contributes to the disease pathogenesis, and its signaling pathway is currently the target of several therapeutic strategies. Although various BCR alterations have been described in B-CLL at the protein level, the mRNA expression levels of tyrosine kinases in B-CLL compared to that in normal CD5-high and CD5-low B-lymphocytes remain unknown. In the current study, we measured the mRNA expression levels of CD79A, CD79B, LYN, SYK, SHP1, and ZAP70 in purified populations of CD5-high B-CLL cells, CD5-low B-cells from the peripheral blood of healthy donors, and CD5-high B-cells from human tonsils...
November 10, 2017: Cancer Medicine
Wen-Di Zhou, Xiang Wang, Xing-Zhen Sun, Jian Hu, Rong-Rong Zhang, Ze Hong
Actein is a tetracyclic triterpenoid compound, extracted from the rhizome of Cimicifuga foetida, exhibiting anticancer activities as previously reported. However, the effects of actein on human leukemia have not been explored before. In this study, the role of actein in regulating apoptosis induction in human leukemia cells was investigated. Actein administration significantly enhanced apoptosis, especially in human leukemia cell line of U937 and the primary human leukemia cells. The promotion was accompanied by caspase-9, caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage, and cytochrome c (Cyto-c) release...
October 10, 2017: International Journal of Oncology
Peng Jin, Hongxi Chen, Jinliang Xie, Cheng Zhou, Xiangrong Zhu
Kidney transplantation is an effective final therapeutic procedure for patients with end-stage kidney failure. Although advanced immunosuppressive therapy is administered following transplantation, certain patients still suffer from acute allograft rejection. MicroRNAs (miRs) have a potential diagnostic and therapeutic value for acute renal allograft rejection; however, their underlying mechanism of action is largely unknown. In the present study, an increased level of miR-650 was identified to be associated with the downregulation of B-cell CLL/lymphoma 11B (BCL11B) expression in acute renal allograft rejection...
October 17, 2017: International Journal of Molecular Medicine
Karol Pal, Vojtech Bystry, Tomas Reigl, Martin Demko, Adam Krejci, Tasoula Touloumenidou, Evangelia Stalika, Boris Tichy, Paolo Ghia, Kostas Stamatopoulos, Sarka Pospisilova, Jitka Malcikova, Nikos Darzentas
Motivation: Sanger sequencing is still being employed for sequence variant detection by many laboratories, especially in a clinical setting. However, chromatogram interpretation often requires manual inspection and in some cases, considerable expertise. Results: We present GLASS, a web-based Sanger sequence trace viewer, editor, aligner and variant caller, built to assist with the assessment of variations in 'curated' or user-provided genes. Critically, it produces a standardized variant output as recommended by the Human Genome Variation Society...
December 1, 2017: Bioinformatics
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