Expression levels of CD38 in T cells predict course of disease in male patients with B-chronic lymphocytic leukemia

Abstract

IntroductionB-cell chronic lymphocytic leukemia (B-CLL) is a neoplastic disease of slowly proliferating CD5 ϩ B cells that develops in the older population. Its clinical behavior is variable, with some patients having an indolent course without any therapy and others a rapidly progressing one probably requiring aggressive treatment. As an underlying mechanism of differential disease activity, genomic aberrations 1 and distinct expression levels of signaling molecules influencing survival as well as proliferation of B-CLL cells have been postulated. Besides the B-cell receptor itself 2,3 and Zap-70, a tyrosine kinase involved in B-cell receptor (BCR) signaling, 4 CD38, initially described as a mediator of leukocyte adhesion to endothelium, 5 was identified as a further candidate, since it induces both survival and proliferation signals in B-CLL cells 6 and its expression and signaling capacity correlate with both progression and response to therapy. 7 Its clinical importance as negative prognostic marker was established by analysis of CD38 expression in large patient cohorts. [7][8][9][10] While the study of malignant cells provides many insights into tumor biology, it has also become clear that transformation and progression of tumors is not an independent process but is controlled by their interactions with the tumor microenvironment (for a recent review see Joyce 11 ). Supporting factors in the microenvironment include stromal and vascular cells as well as infiltrating immune cells. Dependency on such supportive signals should also be relevant in B-CLL, in which close cooperation with other immune cells can be expected from normal behavior of B cells. In the present study, we focused on T cells and their expression of CD38 for the following reasons. (1) CD38 has been identified as an important signaling molecule of T cells. 12 (2) The signaling capacity of T cells has been shown to be dysregulated in B-CLL patients (for a review see Scrivener et al 13 ). Such an aberrant immune control might favor a more aggressive outgrowth of the neoplastic B-cell clone and negatively impact on the clinical outcome of patients. (3) T cells might even deliver antiapoptotic and/or proliferative signals to the neoplastic clone when coming into intimate contact with each other in lymphoid compartments like bone marrow or lymph nodes. 14 We therefore raised the question of whether aberrant expression of CD38 in T cells might also be of prognostic relevance in B-CLL. Patients, materials, and methods Patients and samplesThe study was approved by the local ethics committees (those of the Medical University Innsbruck and Provincial Government of Salzburg, Austria) and conducted according to the Declaration of Helsinki. After providing informed patient consent, 204 consecutive, unselected B-CLL For personal use only. on May 11, 2018. by guest www.bloodjournal.org From patients seen at the Department of Hematology and Oncology, University Hospitals Innsbruck and Salzburg, Austria, between March 2000 and November 2005 were included in t...

Difference in the Relative Distribution of CD4+ T-cell Subsets in B-CLL With Mutated and Unmutated Immunoglobulin (Ig) VH Genes

“…32 Our previous analysis revealed that the CD38 + T cells with such an impact on clinical course were more likely in the CD8 + rather than the CD4 + T-cell population. 32 We now identified a skewing within the CD4 + T-cell pool from naive to memory T cells, again with a pronounced influence on the clinical course and with a previously unrecognized interaction of T cells with the mutational status of Ig VH genes. These data support the important role of T cells in the pathobiology of B-CLL and identify them as potential therapeutic targets given that the molecular mechanisms of the interactions of T cells and tumor cells can be elucidated in future studies.…”

microRNA-34a expression correlates with MDM2 SNP309 polymorphism and treatment-free survival in chronic lymphocytic leukemia

“…The immunoglobulin heavy chain variable region (IgVH) mutational status, CD38 expression, p53 mutations, and SNP309 genotype were determined as previously described. 21,29 For detection of genomic aberrations, interphase fluorescent in situ hybridization (FISH) analysis using the multicolor probe set (Abbott/ Vysis) was performed. Peripheral blood mononuclear cells (PBMCs) were separated by density centrifugation using Biocoll (Biochrom AG).…”

Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia

“…Analysis of the prognostic marker CD38 in CLL cells was performed according to a protocol described previously. 7 Flow-cytometric detection of intracellular forkhead box transcription factor P3 (FoxP3) was performed according to the manufacturer's recommendations (eBioscience, San Diego, Calif). Proliferation of T cells was detected by dilution of carboxyfluorescein diacetate succinimidyl ester as described elsewhere.…”