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 withPIG-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.