3953

LEPR

CD295|LEP-R|OB-R|OBR;leptin receptor;LEPR;leptin receptor

OB receptor|huB219

1p31

protein-coding

Recently, leptin has been shown to play a regulatory role for differentiation within the myeloid and erythroid cell lineage, whereas results of its regulatoryeffects on lymphocytes and related tumor cells have been contradictory. To investigate whether leptin plays a role in acute lymphoblastic leukemia (ALL), we investigated the levels of leptin in plasma with enzyme-linked immunosorbent assays and the expression of the leptin receptor on malignant lymphoblasts with reverse transcriptase polymerase chain reaction (RT-PCR). At diagnosis, the leptin levels of bone marrow-derived plasma in children with ALL were found to be significantly lower than the levels of healthy control subjects (0.92 +/- 0.79 ng/mL versus 3.01 +/- 2.27 ng/mL, respectively). Notably, at complete hematologic remission (at day 33 of chemotherapy), leptin levels had normalized to 2.6 +/- 2.4 ng/mL. To elucidate the underlying mechanism of this phenomenon, we analyzedthe expression of the leptin receptor on the mononuclear cell populations of thepatients. RT-PCR analysis revealed gene expression rates of 33% at diagnosis versus 71% at remission, compared with 100% for healthy control subjects. Results of immunohistochemical staining supported these findings by showing that the tumor clones themselves do not express the leptin receptor. Finally, some hypotheses that might explain the decrease of leptin levels in the presence of the tumor clone are discussed.

PURPOSE: Overweight (body mass index [BMI] 25 to 29 kg/m2) and obesity (BMI > or= 30 kg/m2) frequently follow treatment for childhood acute lymphoblastic leukemia (ALL). Recent studies suggest that risk is most apparent in females treated with cranial radiation at a younger age. Because radiation at a young age may affect the hypothalamus causing leptin receptor insensitivity, we hypothesized that a polymorphism in the leptin receptor (LEPR) gene, Gln223Arg, might influence susceptibility to obesity in survivors of childhood ALL. PATIENTS AND METHODS: We genotyped 600 non-Hispanic white adult ALL survivors enrolled onto the childhood cancer Survivor Study. BMI was compared between those with two copies of the Arg allele to those who had at least one copy of the Gln allele. RESULTS: Female survivors with BMI > or = 25 kg/m2 were more likely Arg homozygous than those with BMI less than 25 kg/m2 (24% v 12%; P =.007). This difference was not observed in males. Moreover, among females treated with > or = 20 Gy cranial radiation, Arg/Arg individuals had six times higher odds of havingBMI > or = 25 kg/m2 (95% CI, 2.1 to 22.0) than those with a Gln allele (P =.04 for interaction). CONCLUSION LEPR polymorphism may influence obesity in female survivors of childhood ALL, particularly those exposed to cranial radiation. Because obesity is associated with increased morbidity and mortality in later life, identification of children at high risk might allow for early targeted interventions.