High interleukin-15 expression characterizes childhood acute lymphoblastic leukemia with involvement of the CNS.
OBJECTIVE
Applying current diagnostic methods, overt CNS involvement is a rare event in childhood acute lymphoblastic leukemia (ALL). In contrast, CNS-directed therapy is essential for all patients with ALL because without it, the majority of patients eventually will experience relapse. To approach this discrepancy and to explore potential distinct biologic properties of leukemic cells that migrate into the CNS, we compared gene expression profiles of childhood ALL patients with initial CNS involvement with the profiles of CNS-negative patients.


METHODS
We evaluated leukemic gene expression profiles from the bone marrow of 17 CNS-positive patients and 26 CNS-negative patients who were frequency matched for risk factors associated with CNS involvement. Results were confirmed by real-time quantitative polymerase chain reaction analysis and validated using independent patient samples.


RESULTS
Interleukin-15 (IL-15) expression was consistently upregulated in leukemic cells of CNS-positive patients compared with CNS-negative patients. In multivariate analysis, IL-15 expression levels greater than the median were associated with CNS involvement compared with expression equal to or less than the median (odds ratio [OR] = 10.70; 95% CI, 2.95 to 38.81). Diagnostic likelihood ratios for CNS positivity were 0.09 (95% CI, 0.01 to 0.65) for the first and 6.93 (95% CI, 2.55 to 18.83) for the fourth IL-15 expression quartiles. In patients who were CNS negative at diagnosis, IL-15 levels greater than the median were associated with subsequent CNS relapse compared with expression equal to or less than the median (OR = 13.80; 95% CI, 3.38 to 56.31).


CONCLUSIONS
Quantification of leukemic IL-15 expression at diagnosis predicts CNS status and could be a new tool to further tailor CNS-directed therapy in childhood ALL.
Cario
Gunnar
G
Department of Pediatrics, University Hospital Schleswig-Holstein, Kiel, Germany.
Izraeli
Shai
S
Teichert
Anja
A
Rhein
Peter
P
Skokowa
Julia
J
Möricke
Anja
A
Zimmermann
Martin
M
Schrauder
Andre
A
Karawajew
Leonid
L
Ludwig
Wolf-Dieter
WD
Welte
Karl
K
Schünemann
Holger J
HJ
Schlegelberger
Brigitte
B
Schrappe
Martin
M
Stanulla
Martin
M
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D019409:Interleukin-15 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D018365:Neoplasm, Residual / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism
D014408:Biomarkers, Tumor; D019409:Interleukin-15; D012333:RNA, Messenger; D012334:RNA, Neoplasm