Evidence for a multistep pathogenesis of chronic myelogenous leukemia

To study the relationship of the Philadelphia chromosome (Ph¹) to the pathogenesis of chronic myelogenous leukemia, multiple B-lymphoid cell lines were established from a patient with Ph¹-positive leukemia who was heterozygous for the X-chromosome-linked enzyme glucose-6-phosphate dehydrogenase. Both A and B types of enzyme were found in a 1:1 proportion in normal tissues, but 45 of 63 (71%) Ph¹-negative B-lymphoid cell lines derived from this patient showed only the single glucose-6-phosphate dehydrogenase (type B) found in the Ph¹-positive leukemic clone. Furthermore, 8 of 33 analyzable lines with B-type enzyme had chromosomal aberrations compared to 0 of 14 lines with A-type glucose-6-phosphate dehydrogenase. These results provide evidence for the suggestion that some cells of the abnormal clone do not express the Ph¹ abnormality. Thus, acquisition of Ph¹ may not be a sufficient cause for the disease. It is possible that at least two steps are involved in the pathogenesis of Ph¹-positive chronic myelogenous leukemia, one causing abnormal proliferation of a clone of pluripotent hematopoietic stem cells and the other inducing Ph¹ in descendents of these progenitors.