Phenotypic differences between healthy effector CTL and leukemic LGL cells support the notion of antigen-triggered clonal transformation in T-LGL leukemia.
T cell large granular lymphocyte leukemia (T-LGL) is a chronic clonal lymphoproliferation of CTL. In many ways, T-LGL clones resemble terminal effector CTL, including down-modulation of CD28 and overexpression of perforin, granzymes, and CD57. We studied the transcriptome of T-LGL clones and compared it with healthy CD8+CD57+ effector cells as well as CD8+CD57- populations. T-LGL clones were sorted based on their TCR variable beta-chain restriction, and controls were obtained by pooling cell populations from 14 donors. Here, we focus our analysis on immunological networks, as immune mechanisms play a prominent role in the etiology of bone marrow failure in T-LGL. Informative genes identified by expression arrays were studied further in an independent cohort of patients using Taqman PCR, ELISA assays, and FACS analysis. Despite a strikingly similar gene expression profile between T-LGL clones and their healthy counterparts, important phenotypic differences were identified, including up-modulation of TNFRS9, myeloid cell leukemia sequence 1, IFN-gamma, and IFN-gamma-related genes, and several integrins/adhesion molecules. In addition, T-LGL clones were characterized by an overexpression of chemokines and chemokine receptors that are typically associated with viral infections (CXCL2, Hepatitis A virus cellular receptor 1, IL-18, CCR2). Our studies suggest that immunodominant LGL clones, although phenotypically similar to effector CTL, show significantly altered expression of a number of genes, including those associated with an ongoing viral infection or chronic, antigen-driven immune response.
Wlodarski
Marcin W
MW
Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. marwlo@gmail.com
Nearman
Zachary
Z
Jankowska
Anna
A
Babel
Nina
N
Powers
Jennifer
J
Leahy
Patrick
P
Volk
Hans-Dieter
HD
Maciejewski
Jaroslaw P
JP
D000328:Adult; D000368:Aged; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D054066:Leukemia, Large Granular Lymphocytic / Q000235:genetics / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016133:Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D004273:DNA, Neoplasm; D009363:Neoplasm Proteins