Clonal Development, Stem-Cell Differentiation, and Clinical Remissions in Acute Nonlymphocytic Leukemia

To determine whether acute nonlymphocytic leukemia develops clonally, to study the pattern of differentiation of the involved stem cells, and to determine whether clinical remissions are true remissions, we studied 27 patients with acute nonlymphocytic leukemia who were heterozygous for the X-chromosome–linked glucose-6-phosphate dehydrogenase. In each case, leukemic blast cells manifested only one type of glucose-6-phosphate dehydrogenase, indicating that the malignant process had developed from a single cell. In six elderly patients, circulating erythrocytes, platelets, or both expressed only the glucose-6-phosphate dehydrogenase found in blast cells, indicating that these leukemias had arisen from stem cells with multipotent differentiative expression. In 16 younger adults and children, erythroid cells and platelets were predominantly derived from normal stem cells. In three other cases, the stem cell that gave rise to leukemic blasts apparently also gave rise to erythroid progenitors but not to mature erythrocytes. Heterogeneity was also found during remissions. In 8 of 13 patients, restoration of nonclonal hemopoiesis and repopulation of the marrow by normal stem cells was observed during remission. In the other five patients, marrow stem cells remained partially or completely clonal, even during remission. These data indicate that acute nonlymphocytic leukemia is a heterogeneous disease with respect to differentiation of the stem cells involved by leukemia and the nature of remissions. (N Engl J Med 1987; 317:468–73.) IN the studies described here, we used X-chromosome inactivation mosaicism to trace the development and cell-lineage relations of acute nonlymphocytic leukemia. The cell "marker" we employed is the X-chromosome–linked enzyme glucose-6-phosphate dehydrogenase. Because the locus for this enzyme is on a portion of the X chromosome that undergoes inactivation in XX somatic cells, females who are heterozygous for the usual B gene ( Gd B) and a variant gene such as Gd A have two populations of cells: in one population, Gd A is active and type A glucose-6-phosphate dehydrogenase is synthesized; in the other, Gd B is active and type B enzyme . . .