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Blood, 1 January 2002, Vol. 99, No. 1, pp. 24-29
PLENARY PAPER
Frequent detection of T cells with mutations of the
hypoxanthine-guanine phosphoribosyl transferase gene in patients with
paroxysmal nocturnal hemoglobinuria
Kentaro Horikawa,
Tatsuya Kawaguchi,
Sonoko Ishihara,
Shoichi Nagakura,
Michihiro Hidaka,
Tadashi Kagimoto,
Hiroaki Mitsuya, and
Hideki Nakakuma
Acquired mutations of the PIG-A gene result in the
hemolysis characteristic of paroxysmal nocturnal hemoglobinuria (PNH). Although the etiology of the mutation(s) is unclear, mutable conditions have been suggested by the coexistence of multiple clones with different mutations of PIG-A and by the appearance of
leukemic clones in patients with PNH. This study sought to test this
hypothesis by examining the frequency of
hypoxanthine-guanine phosphoribosyl transferase (HPRT)
gene mutations, identified by both resistance to
6-thioguanine (6-TG) and gene analysis. T-cell colonies resistant to
6-TG formed in methylcellulose culture were found in 8 (67%) of 12 PNH
patients and 3 (18%) of 17 age-matched healthy volunteers (P < .02, Fisher exact probability test). The incidence
of resistant colonies ranged from 40 to 367 (mean 149, × 10 7) in the 8 patients and from 1 to 16 (mean 7, × 107) in the 3 healthy donors. Thus, the
HRPT gene mutated more frequently in patients with PNH than
in healthy controls (P < .02, Mann-Whitney test).
Analysis of bone marrow cells supported these findings. Like
the PIG-A mutations in PNH, the HPRT mutations
were widely distributed in the coding regions and consisted primarily
of base deletions. Unlike PNH cells, 6-TG-resistant cells expressed
CD59, indicating that the HPRT mutations did not occur in
PNH clones. No correlation was noted between HPRT mutation
frequency and content of therapy received by the patients. It is
concluded that in PNH patients, conditions exist that favor the
occurrence of diverse somatic mutations in blood cells.
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