Kringle IV Encoding Domains in the Apo(a) Gene and Serum Lipoprotein(a) Level Do Not Contribute to Avascular Necrosis of Bone (AVN) in Acute Lymphoblastic Leukemia.

Introdution

Symptomatic AVN occurs as a serious complication of treatment in 4%–12.5% of pediatric cases with ALL. The final common pathway for the development of AVN involves a compromise in the blood flow, leading to infarction. The pathogenesis is multifactorial, including elevated intracortical pressure, vascular occlusion, altered lipid metabolism/fat emboli, hemostatic abnormalities and inhibition of angiogenesis. The difference in incidence of AVN in patients treated according to one and the same protocol suggests a genetic variation as a contribution to the biology of AVN. In one report, familial occurence of bone marrow edema syndrome (early phase of AVN) was associated with elevated levels of lipoprotein(a)[Lp(a)]. Lp(a) is a complex of low-density lipoprotein (LDL) and a high molecular weight glycoprotein called apolipoprotein(a)[apo(a)]. The Lp(a) level is inversely correlated with the kringle IV repeat number in apo(a), that is present as a naturally variation in the population.

Methods

We investigated the Lp(a) levels and the genetic variation in the Apo(a) gene in pediatric patients with and without AVN. DNA from mononuclear cells was isolated from 10 ALL patients with AVN (group I) and 12 patients without AVN (group II), all matched for age, gender and protocol. AVN is defined as pain of the extremities, not related to treatment with vincristine, confirmed by finding typical abnormalities on MRI. The control group consisted of 13 healthy Caucasian subjects (group III). To detect the number of kringle IV repeats pulsed field gel elctrophoresis (PFGE) and Southern blot of genomic DNA was performed. Serum Lp(a) levels were determined by immuno-nefelometric detection method.

Results

The median number of kringle IV repeats (mean of both alleles) did not significantly differ between the three groups: 25 (range 16–37, group I), 24 (range 13–32, group II), 21 (range 10–36, group III). The median Lp(a) levels in ALL patients with AVN versus ALL patients without AVN were respectively 0.085 g/L (range <0.02–0.848) and 0.067 g/L (range <0.02–0.362). Again the difference was not significant.

Conclusion Our results suggest that Lp(a) and genetic polymorphism of apo(a) do not play a mayor role in the pathogenesis of AVN in pediatric ALL.