Project description:The Journal of Experimental Medicine, Volume 194, Number 11, December 3, 2001 1639-1648 Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia Andreas Rosenwald1, Ash A. Alizadeh2, George Widhopf5, Richard Simon6, R. Eric Davis1, Xin Yu1, Liming Yang1, Oxana K. Pickeral1, Laura Z. Rassenti5, John Powell7, David Botstein3, John C. Byrd8, Michael R. Grever9, Bruce D. Cheson10, Nicholas Chiorazzi11, Wyndham H. Wilson12, Thomas J. Kipps5, Patrick O. Brown2,4 and Louis M. Staudt1 The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malignancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising the possibility that CLL comprises two distinct diseases. Using genomic-scale gene expression profiling, we show that CLL is characterized by a common gene expression "signature," irrespective of Ig mutational status, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Nonetheless, the expression of hundreds of other genes correlated with the Ig mutational status, including many genes that are modulated in expression during mitogenic B cell receptor signaling. These genes were used to build a CLL subtype predictor that may help in the clinical classification of patients with this disease.
Project description:B cell chronic lymphocytic leukemia - A model with immune response
Seema Nanda 1, , Lisette dePillis 2, and Ami Radunskaya 3,
1.
Tata Institute of Fundamental Research, Centre for Applicable Mathematics, Bangalore 560065, India
2.
Department of Mathematics, Harvey Mudd College, Claremont, CA 91711
3.
Department of Mathematics, Pomona College, Claremont, CA, 91711, United States
Abstract
B cell chronic lymphocytic leukemia (B-CLL) is known to have substantial clinical heterogeneity. There is no cure, but treatments allow for disease management. However, the wide range of clinical courses experienced by B-CLL patients makes prognosis and hence treatment a significant challenge. In an attempt to study disease progression across different patients via a unified yet flexible approach, we present a mathematical model of B-CLL with immune response, that can capture both rapid and slow disease progression. This model includes four different cell populations in the peripheral blood of humans: B-CLL cells, NK cells, cytotoxic T cells and helper T cells. We analyze existing data in the medical literature, determine ranges of values for parameters of the model, and compare our model outcomes to clinical patient data. The goal of this work is to provide a tool that may shed light on factors affecting the course of disease progression in patients. This modeling tool can serve as a foundation upon which future treatments can be based.
Keywords: NK cell, chronic lymphocytic leukemia, mathematical model, T cell., B-CLL.
Project description:We used high density oligonucleotide arrays to identify molecular correlates of genetically and clinically distinct subgroups of B-cell chronic lymphocytic leukemia (B-CLL). Gene expression profiling was used to profile the five most frequent genomic aberrations, namely deletions affecting chromosome bands 13q14, 11q22-q23, 17p13 and 6q21, and gains of genomic material affecting chromosome band 12q13. A strikingly high degree of correlation between loss or gain of genomic material and the amount of transcripts from the affected regions leads to the hypothesis of gene dosage as a significant pathogenic factor. Furthermore, the influence of the immunoglobulin variable heavy chain (VH) mutation status was determined. A clear distinction in the expression profiles of unmutated and mutated VH samples exists, which can be discovered using unsupervised learning methods. However, when samples were separated by gender, this separation could only be detected in samples from male patients. Since the samples were either hybridized onto HG-U95A arrays or onto HG-U95Av2 arrays, only genes common to both arrays were used for further analysis. This study is described in more detail in Haslinger C, et al. 2004. J Clin Oncol. 22:3937-3949; Series _keyword: CLL, chronic lymphocytic leukemia, immunoglobulin somatic hypermutation, genomic aberrations
Project description:Micro-RNA expression data of CD19 selected B-cells from previously treated and relapsed chronic lymphocytic leukemia patients. We aimed to correlate miR-34a with TP53 mutation status and del17p status. CD19 B-cells from previously treated and relapsed chronic lymphocytic leukemia patients were selected for RNA extraction and hybridization on Affymetrix microarrays.
Project description:THis is a simple ordinary differential equation model describing chemoimmunotherapy of chronic lymphocytic leukemia, including descriptions of the combinatorial effects of chemotherapy and adoptive cellular immunotherapy.
Project description:Large lymphocytic leukemia (LGL) is a chronic clonal lymphoproliferative disorder, characterized by expansion of cytotoxic CD8+ T-cells or NK-cells. We compared gene expression of 3 LGL leukemia patients with STAT3 mutation (Patients 1, 2, and 3), 3 LGL leukemia patients with STAT5b mutation (Patients 4, 5, and 6), and 2 LGL leukemia patients without STAT3/STAT5b mutation (Patients 7 and 8) with CD8 and NK-cell samples from healthy controls to assess different gene expression patterns between samples.
Project description:Expression of stereotyped B cell receptors (BCR), i.e. non-random combinations of immunoglobulin heavy-chain variable (IGHV) genes, complementarity-determining region-3 (HCDR3), and IGV light chains, identifies discrete clusters and represents a peculiar feature of chronic lymphocytic leukemia (CLL). Expression of IGHV3-23 characterized a CLL subset with peculiar molecular and clinical features.
Project description:LYN kinase is a tyrosine kinase, that regulates cellular homeostasis in a context-specific manner. Our group could show, that its expression in the leukemic microenvironment of chronic lymphocytic leukemia contributes to disease progression (Nguyen PH et al.; Cancer Cell; 2016). To analyze the effect of LYN kinase on the leukemia supportive phenotype of the bone marrow stromal cell line HS-5, we generated single cell clones of LYN deficient stroma cells. These cells were analyzed in a Multi-Omic approach, including ARNA-Seq of stromal cells after 72h of coculture with primary human chronic lymphocytic leukaemia (CLL) samples.