Blood, 1 January 2002, Vol. 99, No. 1, pp. 2-2
PNH: "plus ça change, plus c'est la même
chose"
A condition of being given a gentlemen's C to complete my
undergraduate language requirement was that I would never use French in
public. With apologies to Mademoiselle Ashrifé (my French 31 instructor), the findings of Horikawa and colleagues (page 24) proved
irresistible as they reminded me that, with PNH as with most other of
life's enduring dilemmas, "the more things change, the more they
remain the same." The changes in PNH this time are mutations in the
X-chromosomal gene HGPRT. Unlike in PIG-A,
mutations in HGPRT do not contribute to the pathophysiology of PNH; rather, they serve as surrogate markers for the frequency of
somatic mutations occurring in hematopoietic cells. The authors report
that peripheral blood T lymphocytes resistant to 6-TG (an indicator of
mutant HGPRT) were found in 8 of 12 patients with PNH (67%)
but in only 3 of 17 age-matched healthy volunteers (18%). More
remarkably, the incidence of resistant clones was more than 20 times
greater in the PNH patients than in the control group. Analysis of 6-TG
resistance in the bone marrow supported the interpretation that the
frequency of somatic mutations in hematopoietic stem cells is
abnormally high in patients with PNH. Others have reported evidence of
a higher mutational frequency in PNH although the magnitude was less
than that of the current report. Horikawa and colleagues also found
that the types of mutations in HGPRT in PNH patients
(primarily large deletions) were different than in the healthy
controls (single base-pair substitutions).
One of the most remarkable features of PNH is the coexistence in the
same patient of multiple hematopoietic stem cell clones with discrete
mutations in PIG-A. The studies of Dr Nakakuma's group
provide a plausible explanation for why PNH is often an oligoclonal,
rather than monoclonal, disease. But a higher mutational frequency
alone is insufficient to account for the outgrowth of multiple
PIG-A mutant stem cells characteristic of PNH. Principles of
Darwinian evolution must contribute to the process. A powerful selection pressure is at work for multiple PIG-A mutant stem
cells to emerge from the background of an injured bone marrow. Almost certainly the type of injury is specific (immune-mediated), and the
mutant cells have a growth or survival advantage in this setting because of deficiency of one or more glycosyl
phosphatidylinositol-anchored proteins. Delineating the nature of the
selection process will allow us to understand the unique relationship
between PNH and certain other bone marrow failure syndromes,
particularly aplastic anemia. Changes in how we think about PNH
continue to evolve, but our enduring fascination with the intricate
pathophysiology of this elegant disease remains the same.
Charles J. Parker
University of Utah School of Medicine
