RESUMEN
Mesenchymal stromal cells (MSCs) are an essential cell type of the hematopoietic microenvironment. Concerns have been raised about the possibility that MSCs undergo malignant transformation. Several studies, including one from our own group, have shown the presence of cytogenetic abnormalities in MSCs from leukemia patients. The aim of the present study was to compare genetic aberrations in hematopoietic cells (HCs) and MSCs of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients. Cytogenetic aberrations were detected in HCs from 25 of 51 AML patients (49%) and 16 of 43 MDS patients (37%). Mutations of the FLT3 and NPM1 genes were detected in leukemic blasts in 12 (23%) and 8 (16%) AML patients, respectively. Chromosomal aberrations in MSCs were detected in 15 of 94 MDS/AML patients (16%). No chromosomal abnormalities were identified in MSCs of 36 healthy subjects. We demonstrate herein that MSCs have distinct genetic abnormalities compared with leukemic blasts. We also analyzed the main characteristics of patients with MSCs carrying chromosomal aberrations. In view of these data, the genetic alterations in MSCs may constitute a particular mechanism of leukemogenesis.
Asunto(s)
Aberraciones Cromosómicas , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Células Madre Mesenquimatosas/patología , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Cariotipo Anormal , Adulto , Anciano , Anciano de 80 o más Años , Transformación Celular Neoplásica/genética , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 19 , Femenino , Células Madre Hematopoyéticas/patología , Células Madre Hematopoyéticas/fisiología , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Células Madre Mesenquimatosas/fisiología , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Proteínas Nucleares/genética , Nucleofosmina , Adulto Joven , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
OBJECTIVE: Recently, the "epigenetic molecular clock hypothesis" linked increasing DNA methylation in a distinct CpG island in the cardiac-specific homeobox gene (CSX) gene to relative mitotic cell age. To determine mitotic cell age in hematopoietic cells of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients, we assessed differential CSX methylation patterns in these diseases vs age-adjusted healthy controls. MATERIALS AND METHODS: We performed bisulfite pyrosequencing to analyze CSX methylation in CD34(+) and bone marrow (BM) cells from 53 MDS, 62 AML, 77 ALL patients, and 37 controls. RESULTS: Analysis of MDS CD34(+) and BM cells revealed significantly increasing methylation of CSX in controls < MDS low-risk < MDS high-risk < AML. Furthermore, increased differences of CSX methylation between the CD34(+) vs the unselected BM compartment were detected in matched MDS low-risk but not high-risk and AML samples. ALL samples displayed highly elevated CSX methylation levels as compared to controls. CONCLUSIONS: Assessment of mitotic cell age by CSX methylation analysis could reveal novel insights into the distinct progression of hematologic diseases.
