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Clonal Variation, Autoimmunity, and Neoplasia: An Ecology Lesson from Paroxysmal Nocturnal Hemoglobinuria
The immune response is regarded as one line of host defense against cancer. Thus, cancer seen in immunodeficient states is attributed to loss of immune surveillance, and immune augmentation strategies for anticancer therapy are strenuously pursued. In this issue, Dunn and colleagues (1) propose that immune attack might actually confer an ecological advantage on some neoplastic cells in their microenvironment. They suggest that the distinctive neoplastic clones encountered in patients with paroxysmal nocturnal hemoglobinuria (PNH) may gain the upper hand only in bone marrow affected by autoimmune destruction of normal clones. Much additional work will be required to test this notion. Nonetheless, this provocative hypothesis merits comment for what it could imply about host-tumor ecology and about potential unintended consequences of immune augmentation therapies.
Paroxysmal nocturnal hemoglobinuria is an uncommon disorder characterized by intermittent hemolysis, pancytopenia, and thrombosis (2). Hemoglobinuria results from subpopulations of erythrocytes with extreme susceptibility to complement-mediated intravascular hemolysis (3). The condition arises from a neoplastic clone of pluripotent hematopoietic progenitors (4, 5). Differentiated progeny of all lineages lack an overlapping but distinct array of surface proteins and are functionally impaired (6, 7). For example, PNH erythrocytes and platelets lack at least two exterior membrane proteins (CD55 and CD59) that normally impede the complement cascade, and neutrophils are missing leukocyte alkaline phosphatase.
The unifying abnormality is loss by somatic mutation of the glycosylphosphatidylinositol (GPI) anchor, which contains a lipid moiety embedded in the plasma membrane and a sugar residue protruding into the extracellular …
