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MLL-rearranged leukemia is an aggressive malignancy associated with poor outcome, which is refractory to conventional treatment. Melatonin has been proven to exert anti-tumor activity, but the effect of melatonin on MLL-r leukemia and the underlying mechanism remain poorly understood. In this study, melatonin inhibited cell proliferation and induced apoptosis by activating the caspase-dependent apoptotic pathway in MLL-r leukemia cells. Mechanistic investigations revealed that melatonin suppressed the expression of hTERT by abrogating the binding activity of RBFOX3 to the hTERT promoter. Melatonin also blocked NF-κB nuclear translocation and suppressed NF-κB binding to the COX-2 promoter, thereby suppressing the expression of COX-2. In addition, clinical samples revealed that melatonin exerts anti-leukemic activity in primary MLL-r leukemia blasts ex vivo. In vivo, the mice treated with melatonin experienced a larger reduction in leukemic burden than the control group in a MLL-r leukemia xenograft mouse model. Collectively, these results suggest that melatonin inhibits MLL-rearranged leukemia through suppressing the RBFOX3/hTERT and NF-κB/COX-2 signaling pathways. Our findings provide new insights into the role of melatonin for MLL-r leukemia treatment., (Copyright © 2018. Published by Elsevier B.V.)

Objective: Treatment and outcome of infant acute leukemia (IAL) in developed countries have been well documented. However, reports summarizing diagnosis and outcome of IAL in developing countries are limited., Methods: Five hundred ninety seven pediatric patients were diagnosed with acute leukemia in our hospital between January 1997 and June 2008, of which 19 were younger than 12 months. Data from our 19 cases and the Chinese literature were analyzed., Results: Of the 19 cases, 14 had acute lymphoblastic leukemia (ALL) and 5 had acute myeloid leukemia (AML) based on FAB classification. Immunophenotyping and molecular genetic analysis were performed in only 6 cases. Only 16% (3/19) of the infants received treatment. Two infants with immunophenotypic AML who abandoned treatment achieved spontaneous remission without chemotherapy within 2 and 4 months respectively. Combining our data with those from Chinese literature, less than one third of the infants had immunophenotypic and genetic verification of leukemia and 29% (18/63) of them received treatment., Conclusion: Family financial difficulties and physicians' lack of confidence in treatment outcome in IAL contributed to a high treatment abandonment rate and poor outcome. Public health insurance as well as physician education on current IAL treatment strategies may decrease treatment abandonment in China.

FLT3-ITD mutations occur in approximately 30% of acute myeloid leukemia (AML) and are associated with a poor outcome. Currently available FLT3 inhibitors havein vitrobut limited clinical activity in FLT3-ITD AML. Reports have shown that an arsenic trioxide (ATO)/all-trans-retinoic acid (ATRA) combination improves prognosis in acute promyelocytic leukemia, especially with FLT3-ITD, and ATO or ATRA alone enhances apoptosis in FLT3-ITD AML cells treated with FLT3 inhibitors, providing a rationale to investigate the role of ATO/ATRA in FLT3-ITD AML. Here, we demonstrate that an ATO/ATRA combination selectively exerts synergistic cytotoxicity against FLT3-ITD AML cell lines (MV4;11/MOLM-13). The signaling pathways affected by ATO/ATRA include FLT3/STAT5/MYC, FLT3/STAT5/E2F1, FLT3/ERK/ATF5 and FLT3/AKT/ATF5.ATF5 may function as an oncogene in FLT3-ITD AML. Our findings provide experimental evidence that supports further exploration of ATO/ATRA in FLT3-ITD AMLin vivoand warrants a clinical evaluation of regimens comprising an ATO/ATRA combination. [ABSTRACT FROM PUBLISHER]