Cytokine/cytokine receptor gene expression in childhood acute lymphoblastic leukemia: correlation of expression and clinical outcome at first disease recurrence

Background: Recent studies have shown that cytokines/cytokine receptors (C/CR) affect leukemic cell growth and survival. The goal of the current study was to investigate possible correlations between gene expression patterns of C/CR in leukemic cells, clinical features, and outcome in children with acute lymphoblastic leukemia (ALL) at first disease recurrence.

Methods: Between January 1997 and December 2000, bone marrow (BM) samples were collected from 68 children with first ALL recurrence at diagnosis. These patients were enrolled in the ALL-REZ 95-96 disease recurrence trials of the Berlin-Frankurt-Munster study group. C/CR gene expression (interleukin [IL]-7, IL-10, IL-12p40, IL-15, IL-18, IL-7Ralpha, IL-10R1, IL-15Ralpha, interferon-gamma [IFN-gamma], vascular epithelial growth factor [VEGF], Flt1, and transforming growth factor-beta) was quantified by real-time reverse transcriptase-polymerase chain reaction and correlated with protein expression by immunofluorescence.

Results: In comparison with T-lineage ALL specimens, expression of IL-10, IFN-gamma, IL-15Ralpha, and Flt1 was significantly higher in B-cell precursor (BCP) ALL specimens (P <0.01). Among BCP ALL samples, gene expression of IL-7Ralpha and Flt1 was higher in pre-B than in common or pro-B leukemic cells. Moreover, expression levels of VEGF, IL-7Ralpha, IL-10R1, and IL-15Ralpha were lower in lymphoblasts of patients with a combined BM recurrence than in those with an isolated recurrence (P <0.05). Children with IL-15Ralpha expression above the median level had a significantly better probability of event-free survival (0.65 vs. 0.34, P=0.04) and survival (0.71 vs. 0.37, P=0.02) at 5 years.

Conclusions: Expression of distinct C/CR in ALL cells was associated with lineage commitment and differentiation of leukemic cells, as well as with prognosis. It remains to be evaluated whether these prognostic and biologic findings of distinct C/CR expression in leukemic cells also have therapeutical implications for future antileukemic strategies.