Abstract
The major feature of leukemic cells is an arrest of differentiation accompanied by highly active proliferation. In many subtypes of acute myeloid leukemia, these features are mediated by the aberrant Wnt/β-Catenin pathway. In our study, we established the lectin LecB as inducer of the differentiation of the acute myeloid leukemia cell line THP-1 and used it for the investigation of the involved processes. During differentiation, functional autophagy and low β-Catenin levels were essential. Corresponding to this, a high β-Catenin level stabilized proliferation and inhibited autophagy, resulting in low differentiation ability. Initiated by LecB, β-Catenin was degraded, autophagy became active and differentiation took place within hours. Remarkably, the reduction of β-Catenin sensitized THP-1 cells to the autophagy-stimulating mTOR inhibitors. As downmodulation of E-Cadherin was sufficient to significantly reduce LecB-mediated differentiation, we propose E-Cadherin as a crucial interaction partner in this signaling pathway. Upon LecB treatment, E-Cadherin colocalized with β-Catenin and thereby prevented the induction of β-Catenin target protein expression and proliferation. That way, our study provides for the first time a link between E-Cadherin, the aberrant Wnt/β-Catenin signaling, autophagy and differentiation in acute myeloid leukemia. Importantly, LecB was a valuable tool to elucidate the underlying molecular mechanisms of acute myeloid leukemia pathogenesis and may help to identify novel therapy approaches.
Highlights
Acute myeloid leukemia (AML) is the most common type of leukemia comprising 80% of the cases in adults and 15–20% in children
Impressive successes of a new differentiation therapy concept have been achieved in acute promyelocytic leukemia (APL)
LecB induces differentiation and apoptosis of acute monocytic leukemia cells First, we examined the role of LecB in acute myeloid leukemia as some lectins have been shown to act as growth inhibiting and cytotoxic on tumor cells.[22]
Summary
Acute myeloid leukemia (AML) is the most common type of leukemia comprising 80% of the cases in adults and 15–20% in children. Pharmacological doses of all-trans retinoic acid (ATRA) or arsen trioxide target the PML-RARα fusion protein and induce its degradation and thereby the transcription and the terminal differentiation of the immature precursor cells. Using this concept, striking remission rates and long-term survival between 80 and 90% could be achieved.[13,14] In addition, various therapy attempts of ATRA in combination with other chemotherapeutics are in clinical trials to improve the outcome of the classical therapy.[5,15,16] ATRA and arsen trioxide are only clinically successful in the rare APL subtype (5–10%) of AML. LecB induces a very fast growth rate.[31,32] differentiation of monocytic THP-1 cells followed by apoptosis of the differentiated cells
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