Increased Methylation of the <i>c-fms</i>Protooncogene in Acute Myelomonocytic Leukemias

Abstract

DNA methylation provides an epigenetic information possibly involved in differentiation processes and gene regulation. In this study we investigated the methylation state of the c-fms/M-CSF receptor gene in normal human blood cells and leukemias. The methylation pattern of the c-fms gene as detected by isoschizomeric restriction analysis with Mspl/Hpall showed only slight interindividual variations in normal donors, but there were constant differences between granulocytes and monocytes from the same donor. Of 21 acute myelomonocytic leukemias investigated, 85% revealed a methylation pattern different from that of normal monocytes. One or more restriction sites which were at least partly unmethylated in normal monocytes proved to be methylated in leukemic cells. In contrast, leukemias of lymphocytic origin showed hypomethylation of the c-fms gene. There was no correlation between the methylation state of the c-fms gene and its expression at the RNA level, but an increase in monocyte/ macrophage-specific differentiation markers could be observed in those samples which exhibited a methylation pattern similar to that of normal monocytes. The increased DNA methylation within the c-fms gene might reflect the inactivation of differentiation genes in leukemic cell clones, contributing to their maturation arrest. Furthermore, neoplastic hematopoietic cells seem to exhibit lineage-specific differences in c-fms gene methylation.

TCL1 is activated by chromosomal rearrangement or by hypomethylation

“…Hypermethylation of tumor suppressor genes and hypomethylation of oncogenes have been documented (Roberston et al, 2000). In CLL, hypomethylation has been reported at four oncogenes, BCL2, HRAS, CSF1R, and THRA1 (Browett et al 1989;Felgner et al, 1991;Hanada et al, 1993;Lipsanen et al, 1998). Each of these oncogenes showed losses of methylation that varied between samples.…”

Myeloid maturation block by AML1-MTG16 is associated with Csf1r epigenetic downregulation

“…The human CSF1R gene has been found to be aberrantly hypermethylated in leukemic cells (Felgner et al, 1991). For this reason, we evaluated the DNA methylation status of the Csf1r FIRE region in AML1-MTG16-positive cells.…”

Alterations in DNA methylation are early, but not initial, events in ovarian tumorigenesis

“…Indeed, changes in genomic methylation, either focal or global, are one of the most consistent findings in human cancers (Gama-Sosa et al, 1983; Makos et al, 1993;Vertino et al, 1993) and an epigenetic mechanism was proposed whereby such changes may contribute to neoplastic transformation by changing the expression patterns of genes involved in growth control (Antequera et al, 1990;Jones et al, 1990). For example, hypomethylation of several proto-oncogenes including c-myc (Munzel et al, 1991;Sharrard et al, 1992), ras (Bhave et al, 1988), raf (Ray et al, 1994), bcl-2 (Hanada et al, 1993), erb-Al (Lipsanen et al, 1988), and c-fins (Felgner et al, 1991) was reported in various types of cancerous tissues. In addition, expression of several tumour-suppressor genes including p16/CDKN2 (Merlo et al, 1995;Gonzalez-Zulueta et al, 1995;Herman et al, 1994), retinoblastoma (Greger et al, 1989;Sakai et al, 1991) and von Hippel Lindau gene (Herman et al, 1994) can be turned off by methylation.…”