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.

Acquired skewing of X‐chromosome inactivation patterns in myeloid cells of the elderly suggests stochastic clonal loss with age

“…There are two important clinical implications from our findings. Firstly, XCIPs have been used as a tool in the diagnosis of myeloid malignancies by demonstrating clonality ( Janssen et al, 1989;Tefferi et al, 1990;Tsukamoto et al, 1993). Clearly, this is inappropriate in the elderly patient where an imbalanced XCIP in neutrophils but not in T lymphocytes does not necessarily indicate the expansion of an abnormal clone.…”

Antithymocyte globulin for patients with myelodysplastic syndrome

“…The aetiology of MDS is not well understood. Although the underlying defect involves clonal abnormalities in an early haemopoietic progenitor cell, it is unclear how this causes pancytopenia (Greenberg, 1986;Janssen et al, 1989). Marrow cellularity is extremely variable but, unlike SAA, does not correlate with the degree of cytopenia (Tuzuner et al, 1995).…”

Clonal haemopoiesis in normal elderly women: implications for the myeloproliferative disorders and myelodysplastic syndromes

“…These assays provide a means of assessing clonality without any requirement for tumour-specific genetic or cytogenetic markers, and are potentially applicable to all women. X inactivation patterns have been used to demonstrate the clonal origin of numerous haematological malignancies (Dow et al, 1985;Fialkow et al, 1967;Wiggans et al, 1978;Yu et al, 1994), the existence of clonal remission in acute myeloid leukaemia Fearon et al, 1986;Fialkow et al, 1987;, the stem cell origin of both myeloproliferative disorders (Adamson et al, 1976;Fialkow et al, 1981), and myelodysplastic syndromes (Abrahamson et al, 1991;Culligan et al, 1992;Janssen et al, 1989;Tefferi et al, 1990;van Kamp et al, 1992).…”