Evidence for a multistep pathogenesis of a myelodysplastic syndrome

Abstract

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.

Trisomy 12 and structural abnormalities of 13q14 occurring in the same clone in chronic lymphocytic leukaemia

“…One possible conclusion from our data is that neither trisomy 12 nor 13q14 abnormalities are initiating events in leukaemogenesis. This would be analogous to situations in some cases of myelodysplasia where a monoclonal pattern of X chromosome inactivation has been found in both lymphoid and myeloid cells, whereas a karyotypic abnormality has been confined to the myeloid population (Raskind et al, 1984). The first cytogenetic abnormality could involve either chromosome 12 or 13, while a second cytogenetic event could be trisomy 12 in a cell with a 13q abnormality, or a 13q deletion or translocation in a cell which is already trisomic for chromosome 12.…”

Trisomy 14 is a non‐random karyotypic abnormality associated with myeloid malignancies

“…There is, however, no well-established pathophysiological link between the occurrence of most trisomies and the development of human neoplasia. Additionally, it is not clear whether broad genomic instability may precede the detection of karyotype changes (Raskind et al, 1984), so that karyotype change may be a marker for an underlying process predisposing to malignancy, rather than the predisposing event itself.…”

Combined spectral karyotyping and DAPI banding analysis of chromosome abnormalities in myelodysplastic syndrome

“…MDSs with MCAs tend to progress to AML and to confer a poor prognosis regardless of the subtype of the French-American-British (FAB) classification (Nowell et al, 1986;Greenberg et al, 1997). These findings suggest that the accumulation of genetic alterations plays a key role in the development and subsequent progression of MDS (Raskind et al, 1984;Bartram, 1996).…”