Evidence for the Clonal Origin of Chronic Myeloid Leukemia From a Sex Chromosome Mosaic: Clinical, Cytogenetic, and Marrow Culture Studies

Cytogenetic studies on a 7½-yr-old child presenting with clinical and hematological features of chronic myeloid leukemia (CML) revealed a constitutional 46 XY/47 XYY mosaicism in skin, blood, and marrow. A third 46 XY, Ph¹ cell line predominated in the marrow on initial presentation and in subsequent acute transformation. Assessment of granulocytic colony-forming capacity in agar culture revealed that colony-forming cells (CFCs) were greatly increased in the circulation and possessed the abnormal light buoyant density and low susceptibility to tritiated thymidine killing which distinguishes leukemic CFCs from normal. During acute transformation colony-forming capacity was lost but small, poorly differentiated cell clusters persisted in culture. Only 46 XY, Ph¹ metaphase were obtained following cytogenetic analysis of in vitro colonies and clusters displaying leukemic growth characteristics in agar culture. The coexistence of CML and sex chromosome mosaicism in this patient provides further support for the uniclonal origin of CML and indicates that cytogenetic instability implicated in mosaicism may carry an increased risk of further cytogenetic evolution with emergence of the Ph¹ chromosome.