Aberrant DNA Methylation in Chronic Myeloid Leukemia: Cell Fate Control, Prognosis, and Therapeutic Response

Abstract

Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy characterized by the expression of the BCR-ABL1 fusion gene with different chimeric transcripts. Despite the crucial impact of constitutively active tyrosine kinase in CML pathogenesis, aberrant DNA methylation of certain genes plays an important role in disease progression and the development of drug resistance. This article reviews recent findings relevant to the effect of DNA methylation pattern of regulatory genes on various cellular activities such as cell proliferation and survival, as well as cell-signaling molecules in CML. These data might contribute to defining the role of aberrant DNA methylation in disease initiation and progression. However, further studies are needed on the validation of specific aberrant methylation markers regarding the prognosis and prediction of response among the CML patients.

Down-regulation of Protein Tyrosine Phosphatase Receptor Gamma (PTPRG) in Chronic Myeloid Leukemia Patients in The State of Qatar is Due to Aberrant DNA Methylation Mechanism

“…Several studies documented about the effect of DNA methylation pattern of regulatory genes on various cellular activities such as cell proliferation and survival, as well as cell-signaling molecules in CML [43]. Jelinek et al 2011 studied the Methylation levels of 10 genes in CML patients and found that the frequency of methylated genes ranged from 11%-86% as follows: ABL1 (86%), CDH13 (79%), NPM2 (74%), PGRA (66%), TFAP2E (63%), DPYS (54%), PGRB (52%),OSCP1 (30%), PDLIM4 (21%) and CDKN2B (11%), This indicates that there is aberrant methylation of DNA associated with the progression of CML [44].…”

DNA Methylation and Intra-Clonal Heterogeneity: The Chronic Myeloid Leukemia Model

“…The first studies on DNA methylation in CML were performed in blast phase cells, known for their genetic instability. The first analyses on a limited number of genes [ 36 , 37 , 38 , 39 , 40 , 41 , 42 ], reviewed in [ 43 ], suggested the existence of methylation abnormalities in CML. A tendency to DNA hypermethylation was observed in BC compared with CP-CML primary cells.…”

“…Interestingly, although gene mutations can be present already in the pre-leukemic clone, therapeutic resistance to TKI correlates more with mutations occurring during the follow-up than with their initial presence [ 62 ]. The occurrence of these chromosomal/genetic perturbations and/or BCR-ABL point mutations during the progressive phases of the disease might reflect the well-known genetic instability in CML, probably favored by DNA methylation abnormalities [ 37 , 38 , 43 , 63 ].…”

“…These studies found that the promoters of several genes, such as PU-1 [ 79 ] and HOXA4 [ 63 ], were abnormally methylated at CP diagnosis. Overall, DNA methylation abnormalities were more frequent in the progressive phases of the disease, and methylation changes were proposed as markers of CML progression [ 34 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 79 , 80 , 81 , 82 ] and of therapeutic resistance [ 38 , 43 , 63 , 83 ]. Then, the use of more comprehensive methylation profiling approaches revealed more extensive changes, but again, mainly in the progressive phases of the disease [ 34 , 44 ].…”

“…For instance, in chronic lymphocytic leukemia, three prognostic subgroups, identified on the basis of DNA methylation data, globally correlate with other prognostic factors [ 121 , 122 , 123 , 124 , 125 ]. In CML, several studies have identified DNA methylation changes in the promoter of some genes in the advanced phases of the disease, for instance hypermethylation of the ABL1 [ 80 ], cell cycle-regulating genes [ 43 ], CEBPA [ 81 ], PU-1 [ 79 ], CALCA [ 82 ], HOXA4 or HOXA5 [ 63 ] gene promoters. Moreover, global DNA methylation studies have found a clear increase in DNA methylation alterations in BC cells.…”