High Expression of IL-15 Correlates with Disease Recurrence of Adult B-Lineage Acute Lymphoblastic Leukemia

Cytokines are involved in the response to therapy and resistance of leukemic cells as well as their biological behaviour. Interleukin (IL)-15 has been shown to enhance the proliferation of both normal and malignant lymphocytes, thus suggesting a potential role in leukemogenesis and disease progression. In this study, we analyzed the expression of IL-15 in leukemic cells from 87 patients with adult acute lymphoblastic leukemia (ALL) at initial diagnosis. Expression of IL-15 was measured by real-time RT-PCR and normalized to the internal standard b-actin. mRNA levels were correlated with protein expression by western blot analysis. We found that expression of IL-15 correlated significantly with immunophenotype: T-lineage ALL (n=23) had a more than 4-fold higher IL-15 mRNA expression as compared to B-cell precursor (BCP)-ALL (n=64, P<0.001). IL- 15 expression was higher in common and pre-B as compared to pro-B-ALL, and CD1⁺ cortical T-ALL expressed IL-15 much higher than pre-T or mature T-ALL (median values: 0.152, 0.025, and 0.026, respectively). Patients with BCR-ABL⁺ BCP-ALL (n=18) had lower IL-15 expression compared to BCR-ABL⁻ BCP-ALL (n=38, P=0.041). Furthermore, lower expression values of IL-15 were significantly associated with central nervous system involvement (P<0.001). In contrast, higher expression of IL-15 was significantly correlated with mediastinal (P=0.001) and lymph node infiltration (P=0.051), but not with hepatomegaly and splenomegaly. Notably, high IL-15 expression in BCP-ALL correlated strongly with inferior probability of relapse free survival (pRFS) at five years: pRFS 0.17 ± 0.13 (IL-15 expression > median, n=27) versus 0.47 ± 0.13 (< median, n=37) (P=0.008). However, only a weak correlation of the probability of overall survival (pOS) and IL-15 expression was observed (pOS: 0.41 ± 0.11 versus 0 ± 0, P=0.188).

In conclusion, differential expression of IL-15 in adult ALL at diagnosis was associated with clinical features and outcome, in particular relapse free survival. It remains to be evaluated whether IL-15 might be a relevant therapy target, or might be used for risk stratification.