The Prognostic Significance of TET2 Single Nucleotide Polymorphism in Egyptian Chronic Myeloid Leukemia
1 Professor of Hematology, Internal Medicine, Faculty of Medicine, Alexandria University, Egypt.
2 Professor of Pathology, Medical Genetics Center, Faculty of Medicine, Alexandria University, Egypt.
3 Professor of Clinical Pathology, Faculty of Medicine, Alexandria University, Egypt.
4 Hematology, Internal Medicine, Hematology Department, Faculty of Medicine, Taiz University, Yemen.
Received: June 26, 2019
Accepted: November 13, 2019
Mediterr J Hematol Infect Dis 2020, 12(1): e2020004 DOI 10.4084/MJHID.2020.004
| This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm where
pathogenesis is based on the oncoprotein termed BCR‐ABL1. TET2
initiates DNA demethylation and is frequently mutated in hematological
malignancies, including CML. The relation between TET2 acquisition and
CML transformation and/or imatinib resistance is needed to be
The progression of CML into accelerated phase or blastic phase is associated with the acquisition of genetic or epigenetic abnormalities in particular somatic mutations in genes of chromatin modification of DNA methylation in addition to BCR-ABL rearrangement.
TET-2 has pleiotropic roles during hematopoiesis, including stem cells self-renewal, lineage commitment, and terminal differentiation of monocytes. The chromosome 4q24 region containing theTET-2 gene TheTET-2 gene has 11 exons, and the resulting messenger RNA (mRNA) may form three different isoforms due to alternative splicing. TET 2 is part of the non-driver genetic alterations that may influence myeloproliferative neoplasms development and outcome in general.
The Ten – Eleven Translocation TET proteins TET-1,TET-2, TET-3 are α - ketoglutarate and Fe2+ dependent enzymes capable of modifying DNA methylation status. TET family enzymes and 5- hmC are critical in epigenetic regulation during development. Homozygous and heterozygous mutations in TET-2 gene are recurrent events in human hematopoietic malignancies. Most of these mutations decreaseTET-2 enzymatic activity by truncating the protein or affecting its catalytic activity.TET-2 deletion is sufficient to initiate myeloid and lymphoid transformation, including CML. The role of TET2 polymorphism is not fully established according to the prognostic and responsiveness to treatment in the context of myeloid malignancies, mainly CML.
Aim of Work
Materials and Method
Patients were started on Imatinib 400mg per oral daily after confirming the diagnosis and were followed up monthly by CBC, liver and renal function tests as a routine for filling up their prescriptions. At 3 and 6 months, BCR ABL1 IS% was done by real time PCR to monitor response during which no dose adjustments were required, and mild side effects were reported in the form of mild musculoskeletal pain treated by paracetamol.
Statistical analysis. The software of IBM SPSS 20 was used. Data were tested for normality using the Kolmogorov-Smirnov test, Shapiro-Wilk test. Measurement data were displayed in the form of minimum, maximum, mean ± SD. T-test was used for comparing means in parametric data. Qualitative data were displayed in percentages and tested by Pearson's Chi Square and Fisher Exact Test according to the categories and cells estimation %. If the distribution was nonparametric in distribution, measurement data were displayed in the form of median value and range, and the nonparametric test (Mann-Whitney U) was used for comparing median value. Spearman bivariate correlation analysis was used for analyzing correlation. P<0.05 indicated statistical significance.
|Table 1. TET2 single polymorphism patterns for the 3 positions among the three studied groups (CML, and control).|
|Figure 1. Distribution of Single Nucleotide Polymorphism Among the Studied Group.|
|Table 2. Comparison between prognostic factors in CML cases in chronic phase and TET2 polymorphism.|
|Table 3. Comparison between tet2 polymorphism and BCR ABL1 IS% in chronic phase CML.|
In our study, TET2 SNP rs 34402524 among chronic phase CML was either heterozygous 48% or homozygous 46% but was mainly homozygous among the control group (80%) (p=0.012). As for TET2 SNP rs 2454206, wild type in CML and control group were (62.5%, 63.3% respectively) (p=0.046). TET2 SNP rs 61744960 showed a homozygous pattern among all groups (CML 95.8% and control 100%) (p=0.528).
The studied TET2 SNP might be present as part of a germline phenotype influenced by racial background, as noted within the control group. Variations of TET2 SNP between the control group and CML may suggest that CML patients may have lacked or lost these germline phenotypes during leukomogenesis. The three profiles of TET2 and BCR-ABL emergence are possible: TET2 could proceed BCR-ABL in these cases all Ph positive and Ph negative are TET2 mutant. A biclonal disease, in this case, all Ph positive cells are TET2 wild type. BCR-ABL could occur before TET2 mutation suggesting a late diagnosis of CML.
Kutny et al., in 2015 in a study involving 403 patients enrolled in Children’s Cancer Group reported that the 10 SNPs with higher prevalence (4%–54%), only the most prevalent SNP, rs2454206 (A>G, I1762V) was associated with survival. OS was significantly higher for patients with minor allele genotypes (TET2 AG/GG) than those with TET2 AA genotype (60±10% vs. 38±11% at 5 years, log-rank P=0.013 TET2, the genotype was influenced by racial variations. TET2AA genotype occurred in 79% of black vs. 39% of white patients (p<0.001). However, both in black and withe people, the survival was higher in TET2 AG/GG respect to TET AA genotype.
Li et al. from Taiwan in 2011 reported that about 78.6% of patients were diagnosed with TET2 SNP (single nucleotide polymorphism). All SNPs were heterozygous, and only 4 SNP were homozygous; all were in SNP rs2454206 (I1762V).
In our study, as for chronic phase CML, TET2 SNP rs 34402524 homozygous group was significantly related to larger spleen size and BCR-ABL1 IS% levels at initial diagnosis and after six months on follow up after starting TKIs. This suggests that it may play a role in disease progression within Egyptian population (p<0.05). The other TET2 polymorphisms were common too, yet they did not alter the prognostic criteria for CML patients regarding the Sokal score, WBC count, and spleen size (p>0.05).
The present paper is the first to relate TET2 polymorphism to prognostic parameters, and further studies, within the Egyptian population.
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