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CD38 Expression Levels in Chronic Lymphocytic Leukemia B Cells Are Associated with Activation Marker Expression and Differential Responses to Interferon Stimulation

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CD38 Expression Levels in Chronic Lymphocytic Leukemia B Cells Are Associated with Activation Marker Expression and Differential Responses to Interferon Stimulation Leukemia (2005) 19, 2264–2272 & 2005 Nature Publishing Group All rights reserved 0887-6924/05 $30.00 www.nature.com/leu CD38 expression levels in chronic lymphocytic leukemia B cells are associated with activation marker expression and differential responses to interferon stimulation BT Pittner1, TD Shanafelt2, NE Kay2 and DF Jelinek1 1Department of Immunology and Division of Hematology, Mayo Clinic College of Medicine, Mayo Graduate School, Rochester, MN, USA; and 2Department of Internal Medicine, Mayo Clinic College of Medicine, Mayo Graduate School, Rochester, MN, USA CD38, a surface protein whose expression increases upon B cells.14 Lastly, CD38 also exhibits adhesion molecule normal B-cell activation, is a marker of disease aggression in B- properties.15 cell chronic lymphocytic leukemia (B-CLL). Higher percentages of CD38-expressing CLL B cells may be found in lymphoid As we believe that the rate of disease progression might be compartments compared to peripheral blood. Therefore, it is correlated to the proportion of leukemic B cells bearing a more possible that although CLL B cells are resting, CD38 may be a activated phenotype, we have also looked at other activation marker of recent cell activation prior to entry into the periphery. markers on CLL B cells. A variety of cell surface molecules have To address this hypothesis, we examined the association of been shown to play a role in normal B-cell activation and to CD38 expression with other activation antigens identified in increase in expression upon cell activation, for example, CD38, gene expression profiling experiments and include CD18, 16–18 CD49d, CD20, and subunit 5 of the anaphase-promoting CD20, and integrins. Therefore, given that CD38 currently complex/cyclosome. We found that all these markers were serves as a prognostic marker of B-CLL disease aggressiveness, more highly expressed in leukemic B cells from CD38-positive we sought to determine if these or additional activation markers CLL patients. Lastly, because interferon is known to modulate correlate to CD38 expression. Exploratory experiments compar- CD38 expression, we used IFN-a to test the ability of CLL B cells ing the CLL B-cell gene expression profiles of a small cohort of to increase CD38 expression in vitro. Interestingly, IFN uniformly CD38-positive vs uniformly CD38-negative CLL stimulation only modulated CD38 expression in CLL B cells that already expressed CD38. Taken together, these data patients identified several activation marker candidates. These suggest that CD38 is a marker of a more recently activated candidates included CD20, CD18, CD49d, and subunit 5 of the CLL B cell. This in turn may explain the biological and clinical cell cycle-associated cyclosome protein, anaphase-promoting differences between CD38-positive type B-CLL and CD38- complex/cyclosome (APC/C). Although B-CLL is characterized negative type B-CLL. by a massive accumulation of resting leukemic B cells in the Leukemia (2005) 19, 2264–2272. doi:10.1038/sj.leu.2403975; peripheral blood, examination of these activation proteins, published online 6 October 2005 Keywords: B-CLL; CD38; interferon; cell activation; cell cycle including CD38, could shed light on the developmental stage and some of the biological capabilities of these leukemic cells, including their response to environmental factors. Indeed, a recent report suggests that signaling through CD38 leads to extensive surface receptor signaling networks that may function 19 Introduction to promote a pool of proliferating CLL B cells. Since IFN-a modulates CD38 expression levels on normal B cells20 and monocytes21 and may increase CD38 expression In B-cell chronic lymphocytic leukemia (B-CLL), CD38 mem- 22 brane expression levels serve as a prognostic tool. Several levels on leukemic cells, in this study we chose to examine its reports suggest that patients with 7–30% CD38-positive ability to modulate CD38 on various CLL B-cell populations that leukemic cells exhibit a more aggressive disease course and have different levels of membrane CD38 at the onset of culture. have an inferior response to treatment.1–7 However, one study Herein, we report that leukemic clones from CD38-positive B- suggests that even lower percentages of CD38-expressing CLL patients display a phenotype congruent with a more leukemic B cells correlate with poor outcome8 and other studies recently activated B cell and it is exclusively these CD38- suggest that CD38 expression levels will change during the expressing leukemic cells that have a heightened ability to disease course.9–11 Recently, one study showed that CD38- modulate CD38 expression in response to IFN-a. expressing CLL B cells respond to antibody-induced ligation of 12 CD38 with increased cellular signaling. To date, it remains Materials and methods unclear whether CD38 signaling plays a direct physiologic role in B-CLL or serves merely as a surrogate marker of disease Patient and control specimens aggressiveness. CD38 is a type II transmembrane protein that has several Heparinized peripheral blood was obtained from B-CLL patients functions in diverse cell types. First, it acts as an ecto-enzyme under the approval of the Mayo Clinic Institutional Review catalyzing the conversion of NAD þ to cADPR (reviewed in 13 2 þ Board. Peripheral blood mononuclear cells (PBMC) were Deaglio et al ) which in turn induces Ca flux into the cell. isolated by Ficoll density-gradient centrifugation, and PBMC Secondly, upon antibody ligation, CD38 induces phosphoryla- isolated from all B-CLL patients studied were composed of tion of CD19 and prevents apoptosis of germinal center 490% CD5 þ CD19 þ B cells. All patients were assessed by flow-cytometry using PE-conjugated anti-CD38, APC-conju- Correspondence: Professor DF Jelinek, Department of Immunology, gated anti-CD19, FITC-conjugated CD5, and PE-, APC-, and Guggenheim 4, Mayo Clinic College of Medicine, 200 First St SW, FITC-conjugated isotype controls (BD-Pharmingen, San Diego, Rochester, MN 55905, USA; Fax: þ 1 507 266 0981; E-mail: [email protected] CA, USA). Normal PBMC were isolated from discarded buffy Received 5 January 2005; accepted 26 August 2005; published online coats from healthy blood donors. Freshly isolated samples were 6 October 2005 used in all experiments. CD38-positive CLL B cells display an activated phenotype BT Pittner et al 2265 Gene expression profiling of CD38-negative and - analysis of the CD38neg and CD38pos leukemic cells revealed positive patients 499% purity (data not shown). We performed gene expression profiling (GEP; Affymetrix U133A platform) on primary leukemic B cells isolated from Western blotting individual CD38pos and CD38neg patients and optimized identification of differentially expressed genes associated with Magnetic bead-purified CD19-positive CLL B cells were freshly CD38 expression by restricting the gene profiling to patient cells isolated from B-CLL patients that were either uniformly negative that were unimodally negative and positive for CD38 expres- for CD38 expression (n ¼ 5) or uniformly positive (n ¼ 5). Viable sion. In both groups of patients, CD19-positive cells were tonsillar mononuclear cells were obtained from discarded purified using magnetic bead cell sorting on a Miltenyi tonsillar tissue, and the B-CLL-derived MEC-1 cell line23 was AutoMacs prior to isolation of total RNA. To determine genes obtained from the DSMZ, Germany. Cells were directly lysed that appear to be differentially expressed in this set of into 2 Â SDS sample buffer containing 2-mercaptoethanol, and experiments, we used a recently developed model-based lysates were boiled for 5 min and then stored at À201C until algorithm (PAM analysis) that uses the normalized probe-level further use. After polyacrylamide gel electrophoresis and data as well as information about the underlying experimental transfer, the membranes were blotted with anti-APC/C subunit design. 5 (BioLegend, San Diego, CA, USA), then stripped, and subsequently blotted with anti-b-actin (Novus Biologicals, Littleton, CO, USA) for a loading control. Flow-cytometric analysis of surface marker expression Freshly isolated PBMC from B-CLL patients were stained with APC-conjugated CD19, FITC-conjugated CD5, and either a PE- Results conjugated isotype control or PE-conjugated CD38, CD20, CD18, or CD49d (BD Pharmingen). CD38 positivity was defined Patient characteristics and CD38 expression patterns in as any patient sample where the quotient of the mean B-CLL fluorescence intensity (MFI) of the CD38 staining divided by the MFI of the isotype control was greater than 1. For patients The present study included 47 CD38neg and 43 CD38pos B-CLL displaying CD38 bimodal leukemic populations, the total MFI of patients who were untreated or had received the last dose of CD38 staining was used (ie, the fluorescence intensity was chemotherapy more than 1 year previously (Table 1). There averaged for both peaks). For CD49d staining, 47 CD38neg and were no statistically significant differences in sex distribution, 43 CD38pos patient samples were examined. For CD18 staining, age, Rai stage, time from diagnosis, or treatment status in the 33 CD38neg and 22 CD38pos patient samples were examined. two groups defined by CD38 expression. With respect to For CD20, 29 CD38neg and 22 CD38pos patient samples were CD38pos B-CLL patients, the expression patterns of CD38 are examined. The total MFI of each surface marker or isotype known to vary tremendously between B-CLL patients.8,12 control was determined by analyzing viable CD19-positive/ Indeed, the data shown in Figure 1 are illustrative of CD38 CD5-positive cells. The MFI ratio was calculated as follows: MFI expression variability on gated CD19 þ CD5 þ lymphocytes ratio equals the quotient of the total MFI of antisurface marker within and between B-CLL patients, for example, uniformly high staining divided by the MFI of the isotype-matched control. (Figure 1a), intermediate (Figure 1b), or low (Figure 1c) CD38 expression; uniformly negative CD38 expression (Figure 1d); and bimodal CD38 expression where patient leukemic B cells CD38 induction and expression level analysis are both CD38neg and CD38pos (Figure 1e and f).
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