Most randomized trials for acute promyelocytic leukemia (APL) have investigated highly selected patients under idealized conditions, and the findings need to be validated in the real world. We conducted a population-based study of all APL patients in Zhejiang Province, China, with a total population of 82 million people, to assess the generalization of all-trans retinoic acid (ATRA) and arsenic as front-line treatment. The outcomes of APL patients were also analyzed. Between January 2015 and December 2019, 1,233 eligible patients were included in the final analysis. The rate of ATRA and arsenic as front-line treatment increased steadily from 66.2% in 2015 to 83.3% in 2019, with no difference among the size of the center (≥5 or <5 patients per year, p = 0.12) or age (≥60 or <60 years, p = 0.35). The early death (ED) rate, defined as death within 30 days after diagnosis, was 8.2%, and the 3-year overall survival (OS) was 87.9% in the whole patient population. Age (≥60 years) and white blood cell count (>10 × 109/L) were independent risk factors for ED and OS in the multivariate analysis. This population-based study showed that ATRA and arsenic as front-line treatment are widely used under real-world conditions and yield a low ED rate and a high survival rate, which mimic the results from clinical trials, thereby supporting the wider application of APL guidelines in the future.

Abstract. The O(6)-methylguanine-DNA methyltransferase (MGMT)gene is a tumor suppressor gene that is associated with the risk of developing acute myeloid leukemia (AML). However, the association between the methylation status of the MGMT promoter and the chemotherapeutic outcomes of patients with AML remains unknown. In the present study, 30 bone marrow samples derived from patients with AML were collected prior and subsequent to chemotherapy. The methylation status of the MGMT promoter in the bone marrow specimens was determined by methylation-specific polymerase chain reaction. The results indicated that the methylation status of the MGMT promoter was influenced by different chemotherapeutic regimens. The MGMT methylation status of M4 patients (3 out of 6) were more chemosensitive, compared with that of patients with other AML subtypes (M1, 1 out of 3; M2, 0 out of 8; M3, 3 out of 7; M5, 0 out of 3; and M6, 1 out of 3). Age-based analysis revealed that the group aged ≤60 years (7 out of 24 patients) exhibited more methylation changes than patients aged >60 years (1 out of 6). Male patients (4 out of 13) were more susceptible to chemotherapy-induced methylation changes than female patients (4 out of 17). Thus, the methylation status of the MGMT promoter may serve as a potential biomarker to predict the therapeutic outcomes in male AML patients. However, further studies in larger sample sets are required to confirm the present findings.

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Abstract. Aberrant promoter DNA methylation is a major mechanism of leukemogenesis in hematologic malignancies, including acute myeloid leukemia (AML). However, the association between promoter methylation with chemotherapeutic outcomes remains unknown. In the present study, bone marrow samples were collected prior to and following chemotherapy in 30 AML patients. Methylation-specific polymerase chain reaction technology was used to examine the promoter methylation status of adenomatous polyposis col 2 (APC2) and cytochrome P450 family 1 subfamily B polypeptide 1 (CYP1B1). The results revealed no change in the methylation status of the APC2 promoter in patients following various chemotherapy regimens. However, the methylation status of the CYP1B1 promoter changed in response to 6 different chemotherapy regimens. AML patients of the M3 subtype displayed an induction of the CYP1B1 promoter methylation levels more frequently (57.1%) than patients affected by the other subtypes (M1: 33.3%; M2: 12.5%; M4: 16.7%; M5: 0% and M6: 0%). In addition, a higher frequency of male patients (4/13) exhibited modulation of the CYP1B1 promoter methylation status compared with female patients (3/17). Furthermore, of five AML patients with a poor prognosis, two exhibited changes leading to CYP1B1 hypomethylation and two leading to CYP1B1 hypermethylation. By contrast, three other patients exhibited hypermethylation changes along with remission. This may be explained by the different chemotherapy regimens used to treat these patients or by other unknown factors. The present study revealed that CYP1B1 promoter methylation was induced during chemotherapy, whereas the APC2 promoter remained hemimethylated. Furthermore, the changes in CYP1B1 methylation were dependent on the AML subtypes and the gender of the patients. IntroductionPromoter methylation is important in epigenetics and always leads to transcriptional silencing of tumor suppressor genes in acute myeloid leukemia (AML) (1). Although current chemotherapy regimens result in complete remission in many cases, there is no standard and efficient therapy for refractory AML (2). As aberrant DNA methylation is common in AML, clinical trials using epigenetically-targeted therapies have yielded particularly promising results in the treatment of hematopoietic malignancies (3). Several demethylating agents, including azacytidine and decitabine, have been demonstrated to improve AML prognosis (4).Adenomatous polyposis col 2 (APC2) is a tumor suppressor gene, encoding a protein that controls the stability and nuclear export of β-catenin, which is a Wnt signaling pathway transcriptional coactivator (5). Wnt pathway inhibitors are methylated at a high frequency in AML patients (6). The cytochrome P450 family 1 subfamily B polypeptide 1 (CYP1B1) gene, which is a candidate target gene in numerous types of cancers, encodes a member of the cytochrome P450 enzyme superfamily. Furthermore, cytochrome P450 enzymes are involved in drug metabolism and the synthesis of cholesterol, steroids and other l...

Abstract. Previous studies have demonstrated that promoter hypermethylation of tumor suppressor genes contributes to the occurrence and development of acute myeloid leukemia (AML). However, the association of DNA methylation with chemotherapeutic outcomes remains unknown. In the present study, 15 patients with AML were recruited, and the promoter methylation status of cyclin-dependent kinase inhibitor 2B (CDKN2B), solute carrier family 19 member 3 (SLC19A3) and deleted in lung and esophageal cancer 1 (DLEC1) genes was examined prior to and following various chemotherapeutic regimens in order to identify any alterations. The results suggested that chemotherapy-induced hypermethylation of CDKN2B and DLEC1 may be specific to males and females, respectively, and that there were no alterations in SLC19A3 methylation following chemotherapy. These results may provide an improved understanding of gene methylation to guide the development of an individualized chemotherapy for AML. Due to the complexity of AML and the wide range of treatment types, future studies with a larger sample size are required in order to verify the results of the present investigation.