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. With these techniques, we studied a 61-year-old woman with a myelodysplastic syndrome. 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 immunoglobulin 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, erythrocytes , and platelets. Cultured skin fibroblasts and phytohemagglutinin-stimulated lymphocytes were karyotypically normal, but two 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. We hypothesize that at least two events are involved in the pathogenesis of this patient's myelodysplasia: one causing proliferation of a clone of genetically unstable pluripotent stem cells and another inducing chromosomal abnormalities in its descendants.

Previous studies with the X-chromosome-linked glucose-6-phosphate dehydrogenase (G6PD) as a marker of cellular mosaicism demonstrated that polycythemia vera (PV) and essential thrombocythemia (ET) are clonal disorders of bematopoietic stem cells that can differentiate to erythrocytes, granulocytes, and platelets. To determine if the involved stem cells could also differentiate along the B-lymphoid pathway, we studied one woman with PV and one woman with ET. Of 117 Epstein-Barr virus-transformed B-lymphoblastoid lines expressing a single G6PD derived from the patient with PV, 108 expressed G6PD type A, the type characteristic of the abnormal clone. The ratio of 108:9 was significantly different from the one to one ratio predicted for this patient, which suggested that at least some circulating progenitors for Blymphoid cell lines differentiate from the stem cell involved by the disease. Results obtained from the patient with ET were similar-104 of the 109 lymphoblastoid lines monotypic for G6PD expression displayed the enzyme type found in the abnormal clone of marrow cells. Therefore, in these patients, PV and ET, like chronic myelogenous leukemia, involve a stem cell pluripotent for the lymphoid as well as the myeloid series.

In November 1996, word reached the University of Washington that Philip Fialkow and his wife, Helen, had died while trekking in Nepal. Over a 30-year period, Dr Fialkow and his colleagues used the cellular mosaicism resulting from X-chromosome inactivation in females as a marker system to investigate the clonal development of human hematopoietic disorders. This review discusses the impact that these studies have had on our understanding of hematopoietic stem cell relationships and the pathogenesis of human neoplasia in general. To appreciate the special role played by studies on clonality, it is necessary to consider how little was known about the origin of leukemias and myeloproliferative disorders and the limited techniques available for their study in the early to mid 1960s. Dr Fialkow and his coworkers were the first to show that myeloproliferative disorders and acute myelogenous leukemias (AML) are clonal diseases at the time of diagnosis and to elucidate the level of differentiation manifested by the originating cell type. Although the myelodysplastic disorders were found to involve a pluripotent stem cell, heterogeneity was found in the level of stem cell involvement in AML. Evidence was obtained to support a multistep pathogenesis of these diseases as well as a clonal but cytogenetically normal stage in some cases of Ph-positive chronic myelogenous leukemia, AML, acute lymphoblastic leukemia and myelodysplasia.