RESUMO
BACKGROUND AND OBJECTIVES: Clonal hematopoiesis is the hallmark of myelodysplastic syndromes, but the role played by pluripotent stem cells and progenitor cells in these disorders remains unclear. DESIGN AND METHODS: Eight female patients with myelodysplastic syndrome were studied. X-chromosome inactivation patterns were analyzed in peripheral blood granulocytes, T-lymphocytes, single colonies originating from bone marrow progenitors and pluripotent stem cells, using the human androgen receptor locus polymorphism assay. RESULTS: Granulocytes and progenitor cells were monoclonal in 7/8 cases. Immature stem cells showed a non-clonal pattern of X-inactivation and were detectable at diagnosis in the presence of clonal hematopoiesis. T-lymphocyte clonality was heterogeneous. INTERPRETATION AND CONCLUSIONS: In myelodysplastic syndromes, hematopoiesis may be dominated by a neoplastic clone by virtue of its biological advantage over a residual polyclonal, probably still normal, population of immature stem cells still able to grow in vitro.
Assuntos
Células Clonais/patologia , Células-Tronco Hematopoéticas/patologia , Síndromes Mielodisplásicas/patologia , Idoso , Idoso de 80 Anos ou mais , Anemia Refratária/genética , Anemia Refratária/patologia , Anemia Refratária com Excesso de Blastos/genética , Anemia Refratária com Excesso de Blastos/patologia , Células da Medula Óssea/patologia , Técnicas de Cultura de Células , Cromossomos Humanos X/genética , Metilação de DNA , Mecanismo Genético de Compensação de Dose , Feminino , Humanos , Leucócitos Mononucleares/patologia , Síndromes Mielodisplásicas/genética , Neutrófilos/patologia , Fenótipo , Células-Tronco Pluripotentes/patologia , Células-Tronco/patologiaRESUMO
BACKGROUND: Neutrophilic-chronic myeloid leukemia (CML-N) has been described as a CML variant associated both with a distinctive molecular defect of the Philadelphia chromosome and with a more benign clinical course than classic CML. The translocation (9;22) in CML-N results in the transcription of an e19/a2 type BCR/ABL mRNA that codes for a 230-kD BCR/ABL protein (p230). The indolence of the clinical course of patients with CML-N has been disputed. METHODS: The objectives of this study were to quantify and correlate with clinical outcome the p230 mRNA and protein in patients with CML-N, to describe six new patients and the follow-up (with molecular analysis) of five previously reported patients with CML-N, and to review characteristics of all patients with CML-N and p230 BCR/ABL reported to date in the literature. RESULTS: Quantitative polymerase chain reaction assays on specimens from the great majority of patients with CML-N revealed minimal numbers of molecules of p230 BCR/ABL transcripts per total RNA. This also was associated with a lack of detectable p230 BCR/ABL protein in patient specimens, even in one patient who was followed for 16 years after diagnosis. This may explain the milder leukemic phenotype in most patients with CML-N. A review of all 23 patients who had an e19/a2 type BCR/ABL translocation suggested that the low level of p230 BCR/ABL mRNA and the lack of detectable p230 BCR/ABL protein in patients with no additional cytogenetic abnormalities may predict their indolent clinical course. CONCLUSIONS: Patients with p230 positive CML-N have indolent course, probably as a result of low p230 mRNA and protein levels. This supports the need to conduct additional molecular studies, even if cytogenetic studies have revealed t(9;22), because of the prognostic importance of the molecular findings.
