title: Clonal analysis of myelodysplastic syndromes: evidence of multipotent stem cell origin.
abstract: Restriction fragment length polymorphisms (RFLPs) of the X-chromosome genes hypoxanthine phosphoribosyl transferase (HPRT) and phosphoglycerate kinase (PGK) were studied in 34 female patients with primary myelodysplastic syndromes (MDS). Twelve patients (35%) were heterozygous at the HPRT or PGK loci for BamHI or BglI RFLPs, respectively. In eight patients showing PGK polymorphisms, clonality was determined by X-chromosome inactivation analysis. These included patients from different morphologic subtypes: four with refractory anemia (RA), two with RA and ring sideroblasts (RARS), one patient with RA with excess of blasts (RAEB), and one with chronic myelomonocytic leukemia (CMML). A monoclonal pattern of X-chromosome inactivation was observed in seven cases. In a further case characterized by bone marrow hypoplasia, peripheral blood (PB) leukocytes were polyclonal in origin. Following low-dose cytarabine therapy, reversion to polyclonal hematopoiesis was observed in a case of RAEB indicating the presence of residual normal hematopoietic stem cells with the capacity for marrow reconstitution. The clonal relation of lymphoid and granulocyte/monocyte lineages was studied directly in two cases of CMML exhibiting somatic mutations of N-ras or Ki-ras oncogenes. By selective oligonucleotide hybridization to ras gene sequences amplified in vitro by the polymerase chain reaction, a mutated ras allele was demonstrated in PB granulocytes, monocytes, and B and T lymphocytes of both patients. We conclude that MDS arise from a multipotent hematopoietic stem cell with the potential for myeloid and lymphoid differentiation.
authors.affiliation: Department of Pediatrics II, University of Ulm, FRG.
authors.forename: J W
authors.initials: JW
authors.lastname: Janssen
authors.forename: M
authors.initials: M
authors.lastname: Buschle
authors.forename: M
authors.initials: M
authors.lastname: Layton
authors.forename: H G
authors.initials: HG
authors.lastname: Drexler
authors.forename: J
authors.initials: J
authors.lastname: Lyons
authors.forename: H
authors.initials: H
authors.lastname: van den Berghe
authors.forename: H
authors.initials: H
authors.lastname: Heimpel
authors.forename: B
authors.initials: B
authors.lastname: Kubanek
authors.forename: E
authors.initials: E
authors.lastname: Kleihauer
authors.forename: G J
authors.initials: GJ
authors.lastname: Mufti
mesh_terms: D000328:Adult; D000368:Aged; D002469:Cell Separation; D002999:Clone Cells / Q000187:drug effects / Q000473:pathology*; D003561:Cytarabine / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D005260:Female; D011905:Genes, ras; D008040:Genetic Linkage; D005819:Genetic Markers; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D012150:Polymorphism, Restriction Fragment Length; D014960:X Chromosome
chemical_list: D005819:Genetic Markers; D003561:Cytarabine