EVIDENCE FOR A MULTISTEP PATHOGENESIS OF A MYELODYSPLASTIC SYNDROME

Abstract

Somatic cell genetic approaches utilizing the cellular mosaicism present in women heterozygous for glucose-6-phosphate dehydrogenase (G6PD) have provided information relevant to the pathogenesis of some neoplastic disorders. A 61-yr-old woman with a myelodysplastic syndrome was studied. GdB/GdA heterozygosity was demonstrated in skin and cultured T lymphocytes, which exhibited both A and B type G6PD. In contrast, erythrocytes, platelets, granulocytes and marrow nucleated cells displayed almost exclusively G6PD type B. In addition, 21 of 24 Epstein-Barr virus-transformed B lymphoblastoid lines that expressed a single Ig light chain showed only type B G6PD, suggesting that the stem cells involved by this disease were clonal and could differentiate to B lymphocytes as well as to mature granulocytes, erythocytes and platelets. Cultured skin fibroblasts and phytohemagglutinin-stimulated lymphocytes were karyotypically normal, but 2 independent abnormalities were found in marrow 47,XX, + 8 and 46,XX,del(11)(q23). None of 14 type B G6PD lymphoblastoid lines analyzed in detail contained these karyotypic abnormalities, which strongly suggests that a visible chromosomal alteration is not the sole step in the development of this disease. At least 2 events are involved in the pathogenesis of this patient''s myelodysplasia: 1 causing proliferation of a clone of genetically unstable pluripotent stem cells and another inducing chromosomal abnormalities in its descendants.