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.
Wu
Shuling
S
Department of Pediatric Oncology/Hematology, Charité Medical Center, Berlin, Germany. shuling.wu@charite.de
Gessner
Reinhard
R
von Stackelberg
Arend
A
Kirchner
Renate
R
Henze
Guenter
G
Seeger
Karl
K
D000293:Adolescent; D001853:Bone Marrow / Q000737:chemistry; D019070:Cell Lineage; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D007223:Infant; D008297:Male; D009364:Neoplasm Recurrence, Local; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D018121:Receptors, Cytokine / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome
D016207:Cytokines; D012333:RNA, Messenger; D018121:Receptors, Cytokine