Evidence for hypomethylation in two children with acute lymphoblastic leukemia and leukoencephalopathy.
BACKGROUND
The prognosis of patients with acute lymphoblastic leukemia (ALL) in childhood has improved with intensive chemotherapy. In particular, central nervous system (CNS) leukemia has been well controlled by the presymptomatic administration of intrathecal methotrexate (MTX), high dose systemic MTX, and irradiation. However, the prolonged intrathecal administration and/or the administration of high doses of systemic MTX, especially when combined with irradiation, can lead to leukoencephalopathy (LE), a serious CNS complication of such prophylaxis. Because the mechanisms by which MTX causes this complication have not been elucidated, the authors investigated the transmethylation status of the cerebrospinal fluid (CSF) in two children with ALL and LE to investigate the pathophysiology of that disorder.


METHODS
The levels of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) were measured in the CSF of 2 children with ALL and LE, 7 children with ALL only who were undergoing presymptomatic administration of MTX, and 18 reference children in whom diagnostic lumbar puncture was indicated for other reasons. A sensitive, high performance liquid chromatography (HPLC) method was used with fluorescence detection.


RESULTS
The concentrations of SAM in the CSF were lower in the patients with ALL during treatment with MTX compared with the reference children. The SAM levels in the 2 patients with both ALL and LE were slightly lower than the levels in the 7 patients with ALL only. The SAH concentrations in the CSF were higher in the patients with ALL and LE compared with the patients with ALL only and the reference children. The mean concentration of SAH in the CSF was similar in the reference children to that found in the 7 patients with ALL only. The SAM-to-SAH ratios were lower in the 2 patients with ALL and LE and in the 7 patients with ALL only compared with the reference children. The ratios in the patients with ALL and LE were still lower than in those with ALL only, thus providing supporting evidence of hypomethylation in the 2 patients with ALL and LE.


CONCLUSIONS
The data suggest that the treatment of children with ALL using MTX causes subclinical hypomethylation and that progressive hypomethylation in the CNS, as evidenced in the 2 patients with ALL and LE, may be responsible for the demyelination in the LE induced by MTX.
Kishi
T
T
Department of Pediatrics, Hiroshima Memorial Hospital, Hiroshima, Japan.
Tanaka
Y
Y
Ueda
K
K
D002648:Child; D002851:Chromatography, High Pressure Liquid; D019175:DNA Methylation; D015140:Dementia, Vascular / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D012435:S-Adenosylhomocysteine / Q000134:cerebrospinal fluid / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000134:cerebrospinal fluid / Q000378:metabolism
D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine