Blood, 1 August 2002, Vol. 100, No. 3, pp. 741-741
PNH cells are hard to kill
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder
and a most distressing one for the patients who suffer from it. The
mechanism of the intravascular hemolysis that underlies hemoglobinuria is now understood, and we know that PNH is a clonal disorder due to a
somatic mutation in the PIG-A gene. The most perplexing
outstanding question is the mechanism whereby the PNH clone can expand,
to the extent that it can take over the patient's hematopoiesis almost entirely. Nakakuma's group (page 1031) reports a pertinent finding. Nagakura and colleagues used mononuclear cells enriched in natural killer (NK) cells to carry out cytotoxity assays, using as targets 3 human leukemia cell lines (one myeloid, one of B-cell lineage, and one
of T-cell lineage). Then they compared mutant cell lines with
PIG-A mutations, therefore having a PNH-like membrane
phenotype, with the same cell lines in which the phenotype had been
restored to normal by transfection with PIG-A cDNA. In all
cases the rate of killing of the PNH-like cells was significantly less
than that of the non-PNH-like cells. This difference is not due to a
defect in perforin-mediated lysis; it is due, instead, to the fact that PNH-like cells were unable to activate NK cells to the extent that
non-PNH-like cells did.
These results are in keeping with the notion, previously stated over a
decade ago, that in the pathogenesis of PNH there is an obligatory
cooperation of (1) an abnormality intrinsic to the mutant clone and (2)
an abnormality in the marrow environment. A question that remains open
is whether the difference in NK cell activation reported here, which is
in contrast with some previously published data, applies to normal stem
cells (as opposed to cell lines). Finally, one will need to find out
what may cause, in PNH patients in vivo, an increased NK activity
sufficient to cause the demise of normal stem cells, while allowing PNH
stem cells to prosper.
Lucio Luzzatto
Italian National Institute for Cancer
Research
