CADM1 Expression and Stepwise Downregulation of CD7 Are Closely Associated with Clonal Expansion of HTLV-I–Infected Cells in Adult T-cell Leukemia/Lymphoma

Abstract

Purpose: Cell adhesion molecule 1 (CADM1), initially identified as a tumor suppressor gene, has recently been reported to be ectopically expressed in primary adult T-cell leukemia–lymphoma (ATL) cells. We incorporated CADM1 into flow-cytometric analysis to reveal oncogenic mechanisms in human T-cell lymphotrophic virus type I (HTLV-I) infection by purifying cells from the intermediate stages of ATL development. Experimental Design: We isolated CADM1- and CD7-expressing peripheral blood mononuclear cells of asymptomatic carriers and ATLs using multicolor flow cytometry. Fluorescence-activated cell sorted (FACS) subpopulations were subjected to clonal expansion and gene expression analysis. Results: HTLV-I–infected cells were efficiently enriched in CADM1+ subpopulations (D, CADM1posCD7dim and N, CADM1posCD7neg). Clonally expanding cells were detected exclusively in these subpopulations in asymptomatic carriers with high proviral load, suggesting that the appearance of D and N could be a surrogate marker of progression from asymptomatic carrier to early ATL. Further disease progression was accompanied by an increase in N with a reciprocal decrease in D, indicating clonal evolution from D to N. The gene expression profiles of D and N in asymptomatic carriers showed similarities to those of indolent ATLs, suggesting that these subpopulations represent premalignant cells. This is further supported by the molecular hallmarks of ATL, that is, drastic downregulation of miR-31 and upregulation of abnormal Helios transcripts. Conclusion: The CADM1 versus CD7 plot accurately reflects disease progression in HTLV-I infection, and CADM1+ cells with downregulated CD7 in asymptomatic carriers have common properties with those in indolent ATLs. Clin Cancer Res; 20(11); 2851–61. ©2014 AACR.

Polycomb-dependent epigenetic landscape in adult T-cell leukemia

“…11,23 The coordinates have been deposited in the Gene Expression Omnibus database (GSE33615, GSE55851).…”

Effector Regulatory T Cells Reflect the Equilibrium between Antitumor Immunity and Autoimmunity in Adult T-cell Leukemia

“…ATL cells often share the Treg phenotype, i.e., CD3 þ CD4 þ CD25 þ Foxp3 þ (8,9). Although ATL cells may be defined by their expression of CADM1 (10,11), the overlap and differences between Tregs and ATL cells remain unclear.…”

Human T-cell Lymphotropic Virus Type I–Associated Adult T-cell Leukemia–Lymphoma: New Directions in Clinical Research

“…However, SBH can also detect monoclonal integration in a small percentage of HTLV-1 carriers and approximately 10% of HAM/TSP patients (42,43). Flow-cytometric analysis of T cells recently revealed that the expression of CADM1 and stepwise downregulation of CD7 were closely associated with the clonal expansion of HTLV-1-infected cells in ATL, and CADM1 þ cells with the downregulated expression of CD7 in asymptomatic HTLV-1 carriers exhibited common properties to those in indolent ATL carriers (44).…”