Increased Midkine Gene Expression in Childhood Acute Leukemia.

Midkine (MK) is a heparin-binding growth factor and overexpressed in a number of solid tumors, contributing to their growth. Its expression in acute leukemia, however, has not been clarified. We examined relative levels of MK gene expression defined in K562 cells as 1.00 using real-time quantitative polymerase chain reaction (PCR) in 94 children with acute leukemia and compared with those in normal bone marrow (BM; n=18) and peripheral blood (PB; n=10). Median age was 6 years (range, 0–15 years). Diagnosis included B-precursor ALL (n=41), T-ALL (n=14), B-ALL (n=4), Ph¹-ALL (n=6), infant ALL (n=5) and AML (n=24). 8 normal BM samples were separated into CD34+ and CD34− fractions. MK gene expression was detected in normal control samples. Median MK gene expression level was significantly lower in normal PB (2.9×10e-3) than in normal BM (8.0×10e-3) (p<0.01). Expression of MK gene was higher in normal CD34+ BM cells (0.78×10e-3) than in normal unfractionated BM cells (p<0.001). Overexpression of MK was difined as expression at least twice as high as the maximal MK gene expression in normal PB and BM. In 30 of the 41 patients with B-precursor ALL (73.2%), MK gene is overexpressed. We classified B-cell lineage ALL into 3 stage:

1. DR+,CD19+,CD10+,CD20−,slg−,

2. DR+,CD19+,CD10+,CD20+,slg−,

3. DR+,CD19+,CD20+,slg+.

MK gene expression decreased with B-cell lineage differentiation of leulkemic blast. It was also overexpressed in more than half of the patients with FAB M1 and M2 types of AML. In contrast, overexpression of MK gene was observed only in one of the 13 patients with T-ALL and none of the 6 patients with AML-M5. Supporting the possible involvement of MK in carcinogenesis, overexpression of MK may be not only merely assoziated with total development but also related to leukemic transformation of hematopoietic progenitors. Quantification of MK gene by real-time PCR is relatively simple and widely applicable in patients with acute leukemia. This technique offers particular promise as a prognostic marker and a marker for minimal residual disease in children with B-precursor ALL.