Abstract
AML1‐ETO, the most common fusion oncoprotein by t (8;21) in acute myeloid leukaemia (AML), enhances hematopoietic self‐renewal and leukemogenesis. However, currently no specific therapies have been reported for t (8;21) AML patients as AML1‐ETO is still intractable as a pharmacological target. For this purpose, leukaemia cells and AML1‐ETO‐induced murine leukaemia model were used to investigate the degradation of AML1‐ETO by melatonin (MLT), synthesized and secreted by the pineal gland. MLT remarkedly decreased AML1‐ETO protein in leukemic cells. Meanwhile, MLT induced apoptosis, decreased proliferation and reduced colony formation. Furthermore, MLT reduced the expansion of human leukemic cells and extended the overall survival in U937T‐AML1‐ETO‐xenografted NSG mice. Most importantly, MLT reduced the infiltration of leukaemia blasts, decreased the frequency of leukaemia stem cells (LSCs) and prolonged the overall survival in AML1‐ETO‐induced murine leukaemia. Mechanistically, MLT increased the expression of miR‐193a, which inhibited AML1‐ETO expression via targeting its putative binding sites. Furthermore, MLT decreased the expression of β‐catenin, which is required for the self‐renewal of LSC and is the downstream of AML1‐ETO. Thus, MLT presents anti‐self‐renewal of LSC through miR‐193a‐AML1‐ETO‐β‐catenin axis. In conclusion, MLT might be a potential treatment for t (8;21) leukaemia by targeting AML1‐ETO oncoprotein.
Highlights
The t (8;21) translocation, which results in acute myeloid leukaemia (AML)1‐ETO fusion gene, is the most frequent translocation in AML
AML1‐ETO is an important factor for the leukemogenesis through enhancing self‐renewal of leukaemia stem cells (LSCs) in AML patients with t (8;21)
Inhibiting AML1‐ETO may provide a potential therapy for these AML patients
Summary
The t (8;21) translocation, which results in acute myeloid leukaemia (AML)1‐ETO fusion gene, is the most frequent translocation in AML. Extrapineal tissues, including bone marrow and skin, might contribute to MLT levels.[12] The concentration of MLT may reach up to 0.5 nmol/L in mammalian blood at night At this physio‐ logical concentration, MLT affects the biological clock, regulates the immune system, and presents antioxidant actions.[13] MLT influences the physiological function mainly through interaction with two well‐ characterized G protein‐coupled seven‐transmembrane‐domain re‐ ceptors, MT1 and MT2, which inhibit adenylate cyclase.[14] MLT at higher concentration (mM) presents anti‐cancer activity through inhibiting proliferation and inducing apoptosis in multiple types of cancer including leukaemia.[15] MLT enhances the anti‐ leukaemia activity of puromycin in HL‐60 cells.[16] Fusion genes, such as AML1‐ETO and PML‐RARα, play important roles in leukemogene‐ sis. MLT presents anti‐self‐renewal of LSC through miR‐193a‐AML1‐ ETO‐β‐catenin axis in AML cells carrying AML1‐ETO
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