Aberrations in DNA methylation are detectable during remission of acute lymphoblastic leukemia and predict patient outcome

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From: Epigenomics(Vol. 7, Issue 1)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 6,967 words
Lexile Measure: 1720L

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Author(s): Sanne D van Otterdijk aff1 , Jean Norden aff2 , Anne M Dickinson aff2 , Mark S Pearce aff3 , Caroline L Relton aff4 aff5 , John C Mathers aff6 , Gordon Strathdee [*] aff1

Keywords:

CpG island; DNA methylation; leukemia; prognostic marker; remission

While great advances have been made in the survival of childhood acute lymphoblastic leukemia (ALL) patients in recent years [1 ], ALL in the adult population remains difficult to treat successfully. In young adults (25-60 years old), five-year-survival rates of ALL patients are only 30-40% and long-term survival in patients over 60 years old is typically 10% or less [2 ]. Thus, novel treatments and improved methods for patient stratification, to help optimize current therapies, are urgently needed.

Alterations in DNA methylation are a central feature of cancer development. These alterations include genome-wide hypomethylation, in association with dramatic increases in methylation of promoter-associated CpG islands [ 3 ]. Hypermethylation of CpG islands leads to loss of expression of the associated gene and many important tumor suppressors are inactivated by this mechanism [4 ]. Therapeutic strategies aimed at reversing tumor-specific alterations in methylation are being actively explored [5 ] and inhibitors of DNA methylation are now used as standard therapy for patients with myelodysplastic syndrome [6 ]. Alterations in DNA methylation are also of potential clinical use as prognostic markers [7 ], due to their high tumor specificity and comparative ease of detection. For example, the methylation status of the DNA repair gene MGMT is used to predict response to therapy in glioblastoma patients [8 ] and our group has recently shown that methylation-based markers are superior to currently used molecular markers for prediction of outcome in chronic lymphocytic leukemia (CLL) [9 ]. While the extent to which alterations in DNA methylation are early events that drive the process of leukemia development or are secondary changes is unclear [10 ]; recent studies suggest that alterations in DNA methylation are likely to be very early events in leukemia development. For example, a recent study of CLL found that the abnormal patterns of DNA methylation observed at diagnosis were remarkably stable during disease progression, suggesting that CLL-specific aberrant DNA methylation patterns were fixed relatively early in the disease process [11 ]. Furthermore, in healthy volunteers, ageing is associated with alterations in methylation in DNA from peripheral blood that are reminiscent of those seen in leukemia [12 ].

In this study, we investigated DNA methylation changes during the disease course of ALL using matched diagnostic, remission and relapse samples from ALL patients. We observed that remission-specific patterns of altered CpG island methylation can readily be detected and that methylation levels in remission samples correlated significantly with survival of adult ALL patients.

Patients & methods

Sample collection

DNA was purified from bone marrow collected from 24 childhood ALL patients and 21 adult ALL patients (Table 1). Samples were taken at diagnosis, remission and where applicable, relapse. All samples were collected with appropriate ethical approval.

Childhood ALL samples were taken from patients between 1 and 12 years of age,...

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Gale Document Number: GALE|A409374824