Differential Methylation Pattern of ID4, SFRP1, and SHP1 between Acute Myeloid Leukemia and Chronic Myeloid Leukemia

Abstract

To gain insight into the differential mechanism of gene promoter hypermethylation in acute and chronic leukemia, we identified the methylation status on one part of 5'CpG rich region of 8 genes, DAB2IP, DLC-1, H-cadherin, ID4, Integrin α4, RUNX3, SFRP1, and SHP1 in bone marrows from acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) patients. Also, we compared the methylation status of genes in AML and CML using methylation-specific PCR (MSP). The frequencies of DNA methylation of ID4, SFRP1, and SHP1 were higher in AML patients compared to those in CML patients. In contrast, no statistical difference between AML and CML was detected for other genes such as DLC-1, DAB2IP, H-cadherin, Integrin α4, and RUNX3. Taken together, these results suggest that these methylation-controlled genes may have different roles in AML and CML, and thus, may act as a biological marker of AML.

SHP-1 expression accounts for resistance to imatinib treatment in Philadelphia chromosome–positive cells derived from patients with chronic myeloid leukemia

“…Interestingly, SHP-1 protein levels have been found reduced both in several types of hematopoietic tumors [21][22][23]35 and in patients with advanced stage CML with a DNA methylation independent process. 24 Instead, we demonstrate that in the resistant CML cell line the low expression of SHP-1 is strongly associated with hypermethylation status of its promoter region, as previously shown both in patients with acute myeloid leukemia and patients with CML.…”

“…24 Instead, we demonstrate that in the resistant CML cell line the low expression of SHP-1 is strongly associated with hypermethylation status of its promoter region, as previously shown both in patients with acute myeloid leukemia and patients with CML. 23 Indeed, the exposure of the resistant cell line to a demethylating agent can revert this suppression. We demonstrate that, in both the resistant and the sensitive KCL22 cell lines, the activity of the BCR-ABL is completely suppressed by IMA exposure.…”

“…23 Indeed, bisulfite genomic sequencing of the promoter region proves a great difference in the methylation patterns of SHP-1 gene between KCL22-R and -S cell lines; the CpG sites are completely methylated in most sequenced clones derived from KCL22-R DNA, whereas none of the KCL22-S CpG sites are methylated (data not shown). Importantly, when KCL22-R is incubated with the hypomethylating agent 5-Aza-CdR, we observe a great reduction of CpG methylation (supplemental Figure 2B) together with a significant increase of SHP-1 expression at the mRNA (data not shown) and protein levels (supplemental Figure 2C).…”

“…14 SHP-1 promoter methylation causes loss of SHP-1 expression in leukemias, which results in the activation of the JAK/STAT pathway. [19][20][21][22][23] SHP-1 plays a role in CML transformation and progression 24 ; it seems to be physically associated with BCR-ABL 25,26 being able both to block BCR-ABL-dependent transformation and to mediate PP2A-induced BCR-ABL proteasome degradation. 27 In addition, SHP-1 interacts with SHP-2 in a colon carcinoma-derived cell line.…”

Notable roles of EZH2 and DNMT1 in epigenetic dormancy of the SHP1 gene during the progression of chronic myeloid leukaemia

“…The methylation status of the SHP1 promoter is associated with gene dormancy, which is an important mechanism in the development of lymphoma and leukaemia. SHP1 protein expression was completely absent or partially reduced in the majority of types of lymphoma and leukaemia cell lines, such as YS2, IWA3, NK, TomJim, MTI, EDS, and ATLIK (11,12). The present study demonstrated the lack of SHP1 expression in K562 cells.…”