Clonal origin of chronic myelocytic leukemia in man.

Knowledge of whether a tumor is unicellular or multicellular in origin may provide important insight into its pathogenesis. Information relevant to this point can be obtained by studying neoplasms arising in individuals with two or more genetically different cell populations, such as females heterozygous for the X-linked glucose-6-phosphate dehydrogenase (G-6-PD) locus. In these subjects, a given cell or clone of cells shows only one of the two enzyme types seen in a mixture of their cells." 2 For example, electrophoretic analyses of mass cultures of fibroblasts derived from females heterozygous for the A and B genes at the G-6-PD locus show both type A and type B enzyme, whereas analyses of clones originating from single cells derived from the mass cultures show either type A or type B enzyme but never both A and B.2 Thus, neoplasms arising from a single cell in heterozygous females should exhibit only one enzyme type, while those with a multicellular origin should contain both enzymes. In the first application of this system to the study of neoplasms, Linder and Gartler3 found only type A or type B enzyme in leiomyomas whereas both A and B were found in adjacent normal uterine tissue. This observation strongly suggests a unicellular origin of these tumors. Subsequent studies of this kind provided evidence suggesting a multicellular origin of hereditary trichoepitheliomas,4 carcinoma of the colon,5' I the liver, and the breast,6 and perhaps also of chronic lymphocytic leukemia ;6 in a case of lymphoma, unicellular origin was suggested.5 In this paper we report the application of this system to chronic myelocytic leukemia (CML). In addition to indicating a clonal origin of this malignancy, our results provide strong support for the hypothesis that erythrocytes and granulocytes have a common stem cell. Patients.-Three Negro females heterozygous for the common (A) electrophoretic variant of G-6-PD were studied. They had typical clinical and hematological features of CML. The Philadelphia chromosome was demonstrated in the first two cases, but cytogenetic studies were not done in the third case. Case 1 was a 15-year-old girl who had not yet been treated. At the time of study the peripheral white blood count was 700,000 cells per mm3 of which 6% were myeloblasts, 1% promyelocytes, 1% myelocytes, 44% metamyelocytes, 13% band forms, 31% mature polymorphonuclear cells, and 4% were mononuclear cells. Case 2 was an 86-year-old woman who was being treated with busulfan. At the time of study the peripheral white blood count was 18,000 cells per mm3 of which 3% were metamyelocytes, 7% band forms, 69% mature polymorphonuclear cells, and 21% were mononuclear cells. Case 3 was a 22-year-old woman who had been treated with busulfan for two months. Two weeks before the time of study the peripheral white blood count was 31,500 cells per mm3 of which 3% were myeloblasts, 35% myelocytes, 13% metamyelocytes, 23% neutrophils, 5% basophils, 5% eosinophils, and 16% were mononuclear cells. Methods. Blood was drawn in heparin for preparation of granulocytes7 and in