Journal of Pediatric Hematology/Oncology:
Is Methylation the Key to CD10 Loss?
Papandreou, Christos N. MD, PhD*; Nanus, David M. MD†
*Division of Medical Oncology, University Hospital of Larissa, Larissa, Greece
†Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY
Reprints: David M. Nanus, MD, Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY (e-mail: email@example.com).
Neutral endopeptidase or CD10 is a 90 to 110 kD zinc dependent cell-surface metallopeptidase that cleaves peptide bonds on the amino side of hydrophobic amino acids. Initially identified as the common acute lymphoblastic leukemia antigen, CD10 is normally expressed by early-B, pro-B, and pre-B lymphocytes and by lymph node germinal centers, reflecting a biphasic pattern of CD10 expression in B-cell differentiation. Expression of CD10 by leukemic cells is indicative of the differentiation stage of normal lymphopoiesis from which the malignant cell derives.1 Thus, CD10 is found on non-T-cell ALL cells which derive from pre-B lymphocytes, and on germinal center-related non-Hodgkin lymphoma such as Burkitt lymphoma and follicular lymphoma, but not on leukemia cells or lymphomas, which originate in more mature B cells.
Mixed lineage leukemia (MLL) abnormalities occur in approximately 50% of childhood pro-B ALL and are predominantly restricted to a CD10-negative immunophenotype, suggesting an immature B cell of origin.2 However, half of MLL possess complete IgH gene arrangements indicative of a more mature origin. This contradiction suggests that expression of CD10 may be down-regulated in a transformed MLL cell derived from a more mature B cell. In the study reported in this issue, Ikawa and colleagues3 investigated 4 cases of infant MLL for the cause of CD10 silencing. They found dense methylation of both the type 1 and type 2 CD10 promoters. Sequence analysis of the 5′-regulatory region of the NEP gene previously identified a CpG-rich sequence. Taylor et al4 reported CD10 promoter methylation in a variety of lymphoid malignancies. CD10 methylation as a cause of gene silencing has also been found in a variety of other cell types, including prostate cancers,5,6 rat hepatocellular carcinoma cells,7 and murine cerebral endothelial cells,8 suggesting that epigenetic silencing of CD10 may be a common mechanism of regulating CD10 expression.
CD10 is developmentally regulated in both hematopoetic and epithelial progenitor cells. Two separate regulatory regions control the transcription of 5′ alternatively spliced NEP transcript. These type 1 and type 2 NEP regulatory regions are both characterized by the presence of multiple transcription initiation sites, the absence of classic TATA boxes and consensus initiator elements, and are believed to control tissue-specific expression.9 The close association of the CpG-rich region and potential Sp1-binding sites in the type 2 regulatory region had suggested that methylation may play a role in Sp1 binding to the type 2 promoter and in controlling CD10 transcription. Ikawa et al3 now provide convincing evidence that methylation of transcription factor binding sites contribute to CD10 silencing.
CD10 possesses multiple biologic effects. CD10 substrates include numerous small peptides such as bombesin, endothelin-1, and basic fibroblast growth factor.10 Moreover, CD10's cytoplasmic domain directly interacts with a variety of proteins, including ezrin/radixin/moesin proteins, Lyn kinase, and the phosphatase and tensin homolog (PTEN) protein.11,12 CD10 recruits endogenous PTEN to the cell membrane, leading to prolonged PTEN protein stability and increased PTEN phosphatase activity, resulting in constitutive down-regulation of Akt activity. Consequently, in epithelial cells, CD10 loss from methylation leads to increased cell migration, cell growth, and cell survival, contributing to neoplastic development and progression.13 The precise role of CD10 on hematopoetic cells is not completely known, but presumably is similar to other cell types. Whether CD10 (or lack thereof) is more than just a marker of prognosis or a target for therapy such as using demethylating agents to restore CD10 expression will require further study.
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