Acute Myeloid Leukemia in Adolescents and Young Adults: Challenging Aspects

Ofran, Yishai; Rowe, Jacob M.

doi:10.1159/000360200

Cited by 29 publications

(28 citation statements)

References 34 publications

(35 reference statements)

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“…Chemotherapy with hematopoietic stem cell transplantation for AML is the main treatment and preferred therapy [3]. Along with the high relapse rates in AML patients, the overall 5 year survival rate remains poor, apprpximately 30%-40%, although great advances in medicine and chemotherapy have been achieved [4]. The main cause of therapeutic failure and poor outcomes is the occurrence of chemotherapy resistance in leukemia cells [5].…”

Section: Introductionmentioning

confidence: 99%

MiR-34a Promotes Apoptosis and Inhibits Autophagy by Targeting HMGB1 in Acute Myeloid Leukemia Cells

Liu

Ren

Chen

2017

Cell Physiol Biochem

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Background: MiR-34a is identified as a tumor suppressor gene and involved in acute myeloid leukemia (AML) development. However, the regulatory mechanism of miR-34a in AML is unclear. Methods: The expression of miR-34a and HMGB1 in HL-60, THP-1 and HS-5 cells were detected by qRT-PCR and western blot. Lipofectamine 2000 was used to transfect with miR-34a mimics, miR-34a inhibitor, si-HMGB1, pcDNA 3.1-HMGB1, and corresponding controls. The apoptosis and autophagy of transfected AML cells were assessed by flow cytometry and western blot, respectively. Bioinformatics software and dual luciferase reporter assay were applied to predict and verify the target of miR-34a. The effects of miR-34a mimics or si-HMGB1 on chemotherapy-induced autophagy were further explored in HL-60 cells treated with all-trans retinoic acid (ATRA) along with lysosomal protease inhibitors E64d and pepstatin A. Results: MiR-34a was lower expressed and HMGB1 mRNA and proteins were both higher expressed in HL-60 and THP-1 cells compared with that in HS-5 cells. Higher expression levels of MiR-34 and lower expression levels of HMGB1 both significantly promoted apoptosis and inhibited autophagy in HL-60 and THP-1 cells. Dual luciferase reporter system confirmed that HMGB1 was a potential target of miR-34a. Moreover, overexpression of HMGB1 dramatically reversed the promotion of apoptosis and inhibition of autophagy mediated by higher expression level of miR-34a. Higher expression level of miR-34a and lower expression level of HMGB1 both inhibited chemotherapy-induced autophagy by stimulating the LC3 conversion. Conclusion: MiR-34a promoted cell apoptosis and inhibited autophagy by targeting HMGB1. Therefore, miR-34a may be a potential promising molecular target for AML therapy.

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Section: Introductionmentioning

confidence: 99%

MiR-34a Promotes Apoptosis and Inhibits Autophagy by Targeting HMGB1 in Acute Myeloid Leukemia Cells

Liu

Ren

Chen

2017

Cell Physiol Biochem

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“…Age may be an important risk factor in the selection of therapy for AML (18). Decreased visceral function, drug resistance and poor reactivity among the elders may lead to poor prognosis and high recurrence rate, which results in a poor overall 5-year survival rate for elderly AML patients (3).…”

Section: Discussionmentioning

confidence: 99%

Association between the methylation status of the MGMT promoter in bone marrow specimens and chemotherapy outcomes of patients with acute myeloid leukemia

Hong

Chen

et al. 2016

Oncology Letters

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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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“…The randomized comparison between high dose (200 mg/m 2 /day; days 1–10 every 12 h) and standard dose (100 mg/m 2 /day; days 1–10 every 12 h) cytarabine displayed similar outcomes (overall response was 84% vs. 85%; eight-year survival was 31% vs. 32%) in the MRC AML12 trial [14]. In subgroup analysis of 708 children (2–15 years old) and 541 AYA (16–24 years old) patients, 10 year OS and relapse rates were found to be 47% vs. 59% and 47% vs. 42% ( p > 0.05), respectively [4]. Evaluation of high-dose cytarabine (HiDAC) combined with daunorubicin in induction has been reported by different studies; the Southwest Oncology Group (SWOG; 2 g/m 2 bid × 6 days), the Australian Leukemia Study Group (ALSG; 3 g/m 2 bid on days one, three, five, and seven) and the Eastern Cooperative Oncology Group (ECOG; 3 g/m 2 on days one, three, and five) [6].…”

Section: Remission Induction Therapymentioning

confidence: 97%

“…Although the majority of children with AML are treated in clinical trials, the number of AYAs enrolled in clinical trials is much lower. Reasons for the poor clinical trial participation in adolescents are undefined differences in biology, poor compliance or intolerance of therapy, receiving care at centers without AYA experience and psychosocial needs [4,8]. …”

Section: Managementmentioning

confidence: 99%

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Treatment of Acute Myeloid Leukemia in Adolescent and Young Adult Patients

Seval

Özcan

2015

JCM

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The objectives of this review were to discuss standard and investigational treatment strategies for adolescent and young adult with acute myeloid leukemia, excluding acute promyelocytic leukemia. Acute myeloid leukemia (AML) in adolescent and young adult patients (AYAs) may need a different type of therapy than those currently used in children and older patients. As soon as AML is diagnosed, AYA patient should be offered to participate in well-designed clinical trials. The standard treatment approach for AYAs with AML is remission induction chemotherapy with an anthracycline/cytarabine combination, followed by either consolidation chemotherapy or stem cell transplantation, depending on the ability of the patient to tolerate intensive treatment and cytogenetic features. Presently, continuing progress of novel drugs targeting specific pathways in acute leukemia may bring AML treatment into a new era.

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Acute Myeloid Leukemia in Adolescents and Young Adults: Challenging Aspects

Cited by 29 publications

References 34 publications

MiR-34a Promotes Apoptosis and Inhibits Autophagy by Targeting HMGB1 in Acute Myeloid Leukemia Cells

MiR-34a Promotes Apoptosis and Inhibits Autophagy by Targeting HMGB1 in Acute Myeloid Leukemia Cells

Association between the methylation status of the MGMT promoter in bone marrow specimens and chemotherapy outcomes of patients with acute myeloid leukemia

Treatment of Acute Myeloid Leukemia in Adolescent and Young Adult Patients

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