Risk Of CML Research Articles

GENETIC POLYMORHISM OF CASPASE 8 AND 9 IN IRAQ

This study examined the potential association between polymorphisms of Caspase 9 −293del (rs4645982) and Caspase8−652 6N ins / del (rs3834129) and the danger of acute and chronic myeloid leukaemia in Iraqi population. This case-control study was conducted as 128 (62 acute, and 66 chronic) myeloid leukaemia patient and 65 healthy individuals not infected with cancer. A conventional PCR method was used for detection in this study. The results showed that the Caspase9 −293del (rs4645982) in homozygous and heterozygous deletion genotypes were associated significantly with CML risk ( p= 0.001 and 0.005 ,respectively ) and in homozygous insertion and deletion genotypes of Caspase 8 -652 6N were also associated significantly with CML risk (p= 0.004 and p= 0.00, respectively), while there were non significant association between Caspase9 −293del (rs4645982) and Caspase8 −652 6N (rs3834129) with AML risk in all genotypes of them p > 0.05. These findings suggest that polymorphisms in the Caspase-9 and Caspase-8 genes might be useful markers for determining genetic susceptibility to CML and AML. The results of this study suggest that Caspase9-293 is associated with increased risk of CML in case of homozygous of deletion, and insertion in case of AML, while in Caspase8-652 6N insertion polymorphism are associated with increased risk of both CML and AML in a sample of Iraqi populations.

CML-023: Relationship Between High Body Mass Index (BMI) and Treatment Outcomes in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Dasatinib or Imatinib: Retrospective Analysis of the Phase 3 DASISION Trial

Context In the treatment of CML-CP, early molecular responses to tyrosine kinase inhibitors (TKIs) are associated with improved long-term outcomes, and major molecular response (MMR) at 18 months is an important goal. Obesity may elevate the risk of CML (Strom 2009), and high BMI at diagnosis can delay time to response and reduce MMR rate in patients treated with first-line imatinib (Breccia 2013). In the phase 3 DASISION study ( NCT00481247 ), dasatinib was associated with earlier, more durable, and deeper responses than imatinib (Cortes 2016). Objective Investigate the relationship between BMI and response to first-line TKIs. Design DASISION was an open-label multinational study assessing dasatinib versus imatinib for newly diagnosed CML-CP. Patients were randomized to 100mg dasatinib or 400mg imatinib once daily. In this exploratory analysis, patients were stratified according to high (≥25kg/m2) or normal BMI ( Results Collectively, 259 patients received dasatinib (high BMI, n=109; normal BMI, n=147; unknown, n=3) and 260 received imatinib (high BMI, n=107; normal BMI, n=147; unknown, n=6). Baseline characteristics were balanced within BMI subgroups. High BMI subgroup: significant improvements for dasatinib versus imatinib in median time to MMR (9.2 vs 27.6 months; P Conclusions Improved outcomes were seen in patients with high BMI treated with dasatinib versus imatinib; however, these differences were not seen with normal BMI. These findings need further validation to ascertain the role of BMI in predicting treatment responses in patients with CML-CP. Funding BMS. Previous presentation ASH 2019, HOPA 2020.

Methylenetetrahydrofolate Reductase Gene C677T and A1298C Polymorphic Sequence Variations Influences the Susceptibility to Chronic Myeloid Leukemia in Kashmiri Population.

Background: Methylenetetrahydrofolate reductase (MTHFR) gene is a crucial regulator of folate metabolism and its two prominent polymorphic variants C677T and A1298C lead to decreased MTHFR enzyme activity.Aim of the Study: We planned this case–control study based on numerous studies supporting the association of MTHFR polymorphisms (C677T and A1298C) with CML risk in different ethnic populations. Therefore, the influence of these polymorphisms on CML susceptibility was investigated among Kashmiri population (North India).Materials and Methods: Polymerase chain reaction/restriction fragment length polymorphism (RFLP) technique was employed for genotyping MTHFR C677T and A1298C SNP's in 125 CML patients as against 150 age and gender matched healthy controls.Results: A significant difference was observed in frequency of 677CT genotype between cases and controls [46.4 vs. 27.3% (p = 0.0005)]. Similarly combined 677CT+TT genotype showed significant difference between cases and controls [50.4 vs. 28.6% (p = 0.0002)]. Both MTHFR 677CT and 677CT+TT genotypes imposed greater than 2-fold risk of developing CML (OR = 2.4, 95%CI: 1.46–4.05; OR = 2.5, 95%CI: 1.53–4.16). In case of A1298C SNP, the frequency of 1298AC genotype was higher in controls (64.0%) as compared to CML cases (48.8%) (p = 0.04) and imparted a significant protective role from CML predisposition. Furthermore, haplotype analysis revealed only “677CT/1298AA” haplotype significantly increased the risk of CML predisposition [(p = 0.008) (OR = 3.2, 95% CI: 1.3–7.4)].Conclusion: We conclude that both MTHFR C677T and A1298C polymorphisms may be important genetic modifiers and seem to have a plausible role to confer risk of CML in Kashmiri population, where C677T SNP strongly increases the risk of CML while as A1298C SNP has a protective effect.

The Association of rs2114358 in the miR-1206 Polymorphism to Chronic Myeloid Leukemia.

Association studies with factor candidates have advised that single nucleotide polymorphisms (SNPs) could also be related to CML progression and to the response to medical care. Genetic variation in miR-1206 of both derived and neighborhood SNPs process genes will contribute to the predisposition to cancer. The role of those with the risk of CML has not been extensively studied. Therefore, the aim of this study was to evaluate whether polymorphisms in rs2114358 in pre-miRNAs process genes contribute to the risk of CML. A cross-sectional study was conducted during the period of March 2016 to October 2017 in Khartoum state teaching hospitals. The study population included a total of 420 patients who were previously diagnosed of having CML and 220 cancer-free controls of both gender and were of the same age range. Peripheral blood and bone marrow aspiration samples were collected from patients (254 males, 166 females; median age 58.5 years, range from less than 50 and above 50 years old) and investigated after written informed consent was obtained. Patients were in chronic phase (n=212), accelerated phase (n=125), and blast (n=83). All the patients were under treatment using chemotherapy regiments. The rs2114358 SNP in pre-miRNA was selected for genotyping. The genotyping success rate was 98.3%. Genotype frequencies of the derived SNP and the neighborhood rs2114358 of miR-1206 compared to the controls were significantly different under Hardy-Weinberg Equilibrium (P=0.0001 and 0.0001 respectively). Significant differences were found in allele distributions of this SNP (P<0.01 and P<0.01). In total, the derived variant C allele of rs2114358 (OR=0.168, 95% CI=0.13-0.22) and G allele of neighborhood rs2114358 (OR=0.561, 95% CI=0.44-0.72) in patients' group were associated with an increased risk of CML compared to a control group. Patients with rs2114358 CC genotype (P = 0.0001) or TC (P = 0.0001) and the neighborhood rs2114358 GA genotype (P = 0.0460) or GG (P = 0.0093) were obviously much higher than that of the TT and AA genotype's patients. In conclusion, we discovered the association of SNP rs2114358 in miR-1206 with the risk of CML patients, though more investigations are still required to understand the regulative mechanisms of this miR SNP with the target genes resulting in its dysregulation.

C677T and A1298C polymorphisms of Methylenetetrahydrofolate reductase (MTHFR) gene: Effect and risk to develop chronic myeloid leukemia: A study on Syrian patients

Methylenetetrahydrofolate reductase (MTHFR) gene is essential in folate metabolism. Genetic variations in this gene like 677 C>T and 1298 A>C affect its activity; the latter could act efficiently the DNA methylation and may give susceptibility to different malignancies. Not surprisingly, different studies have described a relationship between the presence of 677 C>T and 1298 A>C MTHFR polymorphisms and the leukemia risk development. However, only few studies have reported this issue in CML.For this work, 118 CML patients and 217 controls were studied. The MTHFR 677 C>T and 1298 A>C polymorphisms were investigated by polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) technique. The frequency of CT and TT genotypes of the MTHFR gene (677 C>T) polymorphism in CML patients was significantly higher compared to controls. Moreover, for the AC and CC genotypes of the MTHFR 1298 A>C polymorphism, a statistically highly significant frequency of 1298 CC genotype was also detected in CML patients when compared to control group (OR = 1.9, 95%, CI = 1.15–3.16, p = 0.01, and OR = 106.92, 95% CI = 14.17–806.64, p = 1.7 × 10−16, respectively). In addition, CML patients with compound 677CT/1298AC, 677TT/1298AA, 677 CC/1298 AC and 677 CC/1298 CC genotypes were related to a high risk of CML (OR = 5.71, 95% CI: 2.751–11.864, p = 0.000001; OR = 59.5, 95% CI: 12.565–282.071, p = 9.8 × 10−12, OR = 1.9, 95% CI: 0.8678–4.549, p = 0.07; OR = 206.8, 95% CI: 26.284–1627.034, p = 1.15 × 10−19 respectively). The frequency of MTHFR 677 C > T and 1298 A > C genotypes was no significantly increased in patients with others phases of CML (accelerated or blastic transformation phases) when compared to the patients in the chronic phase of the disease. We found that both MTHFR 677TT and 1298CC genotypes have been in a high risk to develop a CML in Syrian patients.

Risk of Hematologic Malignancies After Radioiodine Treatment of Well-Differentiated Thyroid Cancer.

Purpose To investigate the risk and outcomes of second hematologic malignancies (SHMs) in a population-based cohort of patients with well-differentiated thyroid cancer (WDTC) treated or not with radioactive iodine (RAI). Methods Patients with WDTC were identified from SEER registries. Competing risk regression analysis was performed to calculate the risks of SHMs that occurred after WDTC treatment and outcomes after SHM development were assessed. Results Of 148,215 patients with WDTC, 53% received surgery alone and 47% received RAI. In total, 783 patients developed an SHM after a median interval of 6.5 years (interquartile range, 3.3 to 11.2 years) from WDTC diagnosis. In multivariable analysis, compared with those undergoing thyroidectomy alone, RAI treatment was associated with an increased early risk of developing acute myeloid leukemia (AML; hazard ratio, 1.79; 95% CI, 1.13 to 2.82; P = .01) and chronic myeloid leukemia (CML; hazard ratio, 3.44; 95% CI, 1.87 to 6.36; P < .001). This increased risk of AML and CML after RAI treatment was seen even in low-risk and intermediate-risk WDTC tumors. Occurrence of AML but not CML in patients with WDTC was associated with shorter median overall survival compared with matched controls (8.0 years v 31.0 years; P = .001). In addition, AML developing after RAI trended toward inferior survival compared with matched controls with de novo AML (median overall survival, 1.2 years v 2.9 years; P = .06). Conclusion Patients with WDTC treated with RAI had an increased early risk of developing AML and CML but no other hematologic malignancies. AML that arises after RAI treatment has a poor prognosis. RAI use in patients with WDTC should be limited to patients with high-risk disease features, and patients with WDTC treated with adjuvant RAI should be monitored for myeloid malignancies as part of cancer surveillance.

Association of glutathione S-transferase (GSTM1 and GSTT1) genes with chronic myeloid leukemia.

Chronic myeloid leukemia (CML), as most of cancers results from a complex interaction between genetic or non genetic factors. Exposures to xenobiotics endogenous or exogenous associated with a reduced individual ability in detoxifying activity, constitutes a risk of developing cancer. It is known that polymorphism of glutathione S-transferases (GSTs) genes affects the detoxification of xenobiotics. Thus, we conducted a case-control study in which 92 patients (Mean age ± SD, 40.62 ± 12.7 years) with CML and 93 healthy unrelated controls (Mean age ± SD, 41.38 ± 13.4 years) have participated. GSTM1 and GSTT1 genotypes were determined by multiplex polymerase chain reaction. Logistic regression was used to assess the possible link between GSTM1 and GSTT1 null genotypes and CML as well as between combined genotypes and CML. GSTM1 null genotype frequency was slightly higher in patients than control (48.9% vs. 40.9%) but, it was not associated with CML (OR 95% CI, 1.4, 0.78-2.48; p = 0.271). Moreover, GSTT1 null genotype frequency showed a similar trend between patients and control (17.4% vs. 9.7%; OR 95% CI, 1.97, 0.82-4.71; p = 0.13). Surprisingly, GSTT1 null genotype was significantly associated with the risk of CML in males (OR 95% CI, 5, 1.25-20.1; p = 0.023). The combined GSTM1 present/GSTT1 null genotype was found to have a limited effect against the risk of CML (OR 95% CI, 0.3, 0.08-0.99; p = 0.049). Our findings have shown that GSTT1 null genotype might be a risk factor of CML in males. While, GSTT1 present genotype might be considered as protective against CML. However, further studies with a large sample size are needed to confirm our findings.

CAT, GPX1, MnSOD, GSTM1, GSTT1, and GSTP1 genetic polymorphisms in chronic myeloid leukemia: a case-control study.

Oxidative damage at the DNA level may be promoted by high levels of reactive oxygen species (ROS), leading to genomic instability and increased neoplastic risk. Superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) enzymes are implicated in the prevention of DNA damage by ROS. The aim of the study was to investigate the relationships between CAT C262T, GPX1 Pro198Leu, MnSOD Ala16Val, GSTM1, GSTT1, and GSTP1 Ile105Val polymorphisms and the risk of CML. No association was observed between CML and variant genotypes of GPX1, MnSOD, GSTM1, and GSTT1 polymorphisms in any of the investigated cases. Our study suggests that the homozygous variant genotype of the GSTP1 Ile105Val gene polymorphisms may be associated with the risk of developing CML (OR = 2.5; 95% CI = 1.08–5.7; P value = 0.02), while the heterozygous genotype of the CAT C262T polymorphism seems to have a protective effect against CML (OR = 0.59, 95% CI = 0.39–0.89, P value = 0.01). In most cases, no association was found between laboratory parameters and prognostic factors and the variant genotype of investigated gene polymorphisms. We concluded that CAT, GPX, MnSOD, GSTM1, and GSTT1 gene polymorphisms are not associated with the risk of CML. Variant genotype of the GSTP1 Ile105Val gene polymorphisms may contribute to the risk of developing CML.

Polymorphism of XRCC1, XRCC3, and XPD genes and risk of chronic myeloid leukemia.

The genetic polymorphisms of X-ray repair cross complementing group 1 (XRCC1), X-ray repair cross complementing group 3 (XRCC3), and xeroderma pigmentosum complementation group D (XPD) repair genes may lead to genetic instability and leukemogenesis. The purpose of the study was to evaluate the association between XRCC1 Arg399Gln, Arg280His and Arg194Trp, XRCC3 Thr241Met, and XPD Lys751Gln polymorphisms and the risk of developing CML in Romanian patients. A total of 156 patients diagnosed with CML and 180 healthy controls were included in this study. We found no association between CML and XRCC1 or XRCC3 variant genotypes in any of the investigated cases. A significant difference was observed in the variant genotype frequencies of the XPD Lys751Gln polymorphism between the patients with CML and control group (for variant homozygous genotypes, OR = 2.37; 95% CI = 1.20–4.67; P value = 0.016 and for combined heterozygous and variant homozygous genotypes, OR = 1.72; 95% CI = 1.10–2.69; P value = 0.019). This was also observed when analyzing the variant 751Gln allele (OR = 1.54; 95% CI = 1.13–2.11; P value = 0.008). Our results suggest that the XPD Lys751Gln variant genotype increases the risk of CML.

GSTP1 (Ile105Val) Gene Polymorphism: Risk and Treatment Response in Chronic Myeloid Leukemia

Background: Genetic variation influencing individual susceptibility to chemical carcinogens is one of the main factors leading to cancer development. The glutathione S-transferases (GSTs) are a family of enzymes belonging to phase II enzymes involved in detoxification of xenobiotics. A significant relationship is observed between the risk of developing cancer and genetic polymorphisms within GSTs. Methods: In this study, we investigated the influence of inherited GSTP1 (Ile105Val) gene polymorphism on the susceptibility to CML in Egypt in 40 CML patients (20 children and 20 adults), together with 40 healthy controls using a [PCR-RFLP] assay. Results: We found that the mutant type (IIe/Val, Val/Val) was significantly higher in CML patients (67.5%) compared to controls (35%) (p = 0.004); [odds ratio 3.9; 95% CI: 1.5 - 9.7]. The mutant type was associated with more advanced phases in disease and with both worse hematological and cytogenetic responses when compared to the wild type (p = 0.03, p = 0.05, and p 0.001, respectively). Conclusion: GSTP1 (Ile105Val) gene polymorphism conferred a significant association with increased risk of CML and is associated with worse prognosis. Further studies on the functional consequences of this genetic polymorphism would pave the way to declare its role in the pathogenesis of CML or as a possible predictor for response to therapy.

Genetic polymorphism of CYP3A5 in Indian chronic myeloid leukemia patients

CYP3A5 is an important genetic contributor to inter-individual differences in CYP3A-dependent clinically important drugs of metabolism and also of various endogenous compounds and environmental contaminants. The CYP3A5*3 allele results in a truncated protein with loss of CYP3A5 expression and CYP3A5*6 is associated with lower CYP3A5 catalytic activity. The polymorphism analysis was performed by PCR-RFLP and some representative cases by direct sequencing. Our case control study involved 183 consecutive North Indian CML patients in chronic phase of disease and 208 geographically and racially matched healthy controls. PCR-RFLP was carried out to determine the frequency of CYP3A5*3 and CYP3A5*6 genotypes. The relationship between these allelic variants and risk of CML was assessed by means of odds ratio (OR) with 95% confidence limits calculated by logistic regression. The frequencies of CYP3A5*1/*1, CYP3A5*1/*3, and CYP3A5*3/*3 genotypes in CML and controls were examined, and the quantitative comparison of the frequency distributions between CML versus control were performed, showing no significant differences among these comparison pairs (P = 0.88, 0.65, and 0.80, respectively). However, we did not find the CYP3A5*6 allele in any of the controls and leukemia patients. It is concluded that there is no association of this polymorphism with the risk of chronic myeloid leukemia.

Genetic variants in the candidate genes of the apoptosis pathway and susceptibility to chronic myeloid leukemia

AbstractChronic myeloid leukemia (CML) is a clonal myeloproliferative disorder, characterized by the presence of BCR/ABL fusion gene. It is unclear which cellular events drive BCR/ABL gene translocation or initiate leukemogenesis in CML. Bcl-2 promotes survival of hematopoietic stem cells. Accordingly, apoptosis-related pathway may involve in the leukemogenesis of CML. In the current study, we evaluated 80 single nucleotide polymorphism (SNP) markers involved in the pathways of apoptosis (n = 30), angiogenesis (n = 7), myeloid cell growth (n = 14), xenobiotic metabolism (n = 13), WT1 signaling (n = 7), interferon signaling (n = 4), and others (n = 5) in 170 CML patients and 182 healthy controls. In a single-marker analysis, the following SNPs were identified including VEGFA, BCL2, CASP7, JAK3, CSF3, and HOCT1. In the multivariate logistic model with these SNPs and covariates, only BCL2 (rs1801018) was significantly associated with the susceptibility to CML (P = .05; odds ratio [OR] 2.16 [1.00-4.68]). In haplotype analyses, haplotype block of BCL2 consistently showed significant association with the susceptibility to CML. Risk allele analysis showed that a greater number of risk alleles from BCL2 SNP correlated to increasing risk of CML (overall P = .1, OR 1.84 [1.06-3.22] for 3-4 risk alleles vs 0-1 risk alleles). The current study indicated that BCL2 SNP seemed to be associated with increasing susceptibility to CML.

MTHFR 677CC/1298CC Genotypes Are Highly Associated with Chronic Myelogenous Leukemia: A Case-Control Study in Korea.

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in folate metabolism and DNA methylation. Studies on MTHFR polymorphism in leukemia have largely focused on the protective role of MTHFR polymorphism in ALL. We evaluated the C677T and A1298C polymorphisms using the TaqMan® allelic discrimination assay in various malignancies. The study population included 115 subjects with CML, 200 with AML, 196 with MM and 434 healthy control subjects. The frequency of 1298 CC was statistically significantly higher in subjects with CML than that of the controls (OR = 5.12, 95% CI: 1.75–14.9, P value =.003). Of note, the frequencies of 677CC/1298CC genotype was statistically significantly higher in subjects with CML, AML and MM than that of the controls (OR = 8.8, 3.5, 3.83, P value =.002, 0.036, 0.023, respectively). Our results demonstrate that the MTHFR 1298CC homozygote variant is strongly associated with an increased risk of CML, while MTHFR C677T does not significantly affect the risk of CML. Moreover, we demonstrated that MTHFR 677CC and 1298CC genotype might have combined effect on risk of CML, AML and MM and it is inferred that the A1298C may play a different role in carcinogenesis, depending on the types of organs involved, the types of disease entities and the genotype of C677T.

Therapy-Related Chronic Myeloid Leukemia: An Epidemiological, Clinical and Pathogenetic Appraisal

Second primary cancers represent an important complication of modern chemotherapy and radiotherapy. Therapy-related (tr) leukemias are among the most common second malignancies in both pediatric and adult populations. Whereas a reasonable amount of data is available regarding the epidemiology, molecular pathogenesis, clinical behavior and response to therapy of second primary acute leukemias, very little is known about therapy-related chronic myeloid leukemia (tr-CML). A better characterization of this entity could increase our understanding about the mechanisms of carcinogenesis, specially the induction of specific genetic abnormalities, e.g., BCR-ABL fusion, following chemotherapy and/or radiotherapy exposure, could facilitate the investigation of the kinetics of the development of CML, and also provide a model to study molecular events that might precede its development. Review of 32 tr-CML cases suggests that there are no clinically appreciable differences between tr-CML and de novo CML cases. Analysis of large epidemiological studies that investigated the risk of second primary leukemias has not shown any clear evidence of a higher risk of CML among individuals who underwent treatment for a primary cancer over the general population. The cancer-predisposing syndromes, the detection of BCR-ABL transcripts in healthy individuals, and the induction in vitro of BCR-ABL fusions by ionizing radiation, are all discussed in the context of tr-CML. Finally, the need for a large epidemiological study to specifically assess the risk of developing second primary CML after chemotherapy and/or radiotherapy is stressed.