BackgroundCurrent conventional chemotherapy for acute myeloid leukemia (AML) can achieve remission in over 70% of patients, but a majority of them will relapse within 5 years despite continued treatment. The relapse is postulated to be due to leukemia stem cells (LSCs), which are different from normal hematopoietic stem cells (HSCs). LIN28B is microRNA regulator and stem cell reprogramming factor. Overexpression of LIN28B has been associated with advance human malignancies and cancer stem cells (CSCs), including AML. However, the molecular mechanism by which LIN28B contributes to the development of AML remains largely elusive.MethodsWe modulated LIN28B expression in AML and non-leukemic cells and investigated functional consequences in cell proliferation, cell cycle, and colony-forming assays. We performed a microarray-based analysis for LIN28B-silencing cells and interrogated gene expression data with different bioinformatic tools. AML mouse xenograft model was used to examine the in vivo function of LIN28B.ResultsWe demonstrated that targeting LIN28B in AML cells resulted in cell cycle arrest, inhibition of cell proliferation and colony formation, which was induced by de-repression of let-7a miRNA. On the other hand, overexpression of LIN28B promoted cell proliferation. Data point to a mechanism where that inhibition of LIN28B induces metabolic changes in AML cells. IGF2BP1 was confirmed to be a novel downstream target of LIN28B via let-7 miRNA in AML. Notably, ectopic expression of LIN28B increased tumorigenicity, while silencing LIN28B led to slow tumor growth in vivo.ConclusionsIn sum, these results uncover a novel mechanism of an important regulatory signaling, LIN28B/let-7/IGF2BP1, in leukemogenesis and provide a rationale to target this pathway as effective therapeutic strategy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0507-y) contains supplementary material, which is available to authorized users.

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PRL-3 (PTP4A3), a metastasis-associated phosphatase, is also upregulated in patients with acute myeloid leukemia (AML) and is associated with poor prognosis, but the underlying molecular mechanism is unknown. Here, constitutive expression of PRL-3 in human AML cells sustains leukemogenesis in vitro and in vivo. Furthermore, PRL-3 phosphatase activity dependently upregulates LIN28B, a stem cell reprogramming factor, which in turn represses the let-7 mRNA family, inducing a stem cell-like transcriptional program. Notably, elevated levels of LIN28B protein independently associate with worse survival in AML patients. Thus, these results establish a novel signaling axis involving PRL-3/LIN28B/let-7, which confers stem cell-like properties to leukemia cells that is important for leukemogenesis. Implications:The current study offers a rationale for targeting PRL-3 as a therapeutic approach for a subset of AML patients with poor prognosis. Mol Cancer Res; 15(3); 294-303. Ó2016 AACR.

Acute myeloid leukemia (AML) is an aggressive disease with an increasing incidence and relatively low 5‐year survival rate. Unfortunately, the underlying mechanism of leukemogenesis is poorly known, and there has been little progress in the treatment for AML. Studies have shown that X‐linked inhibitor of apoptosis (XIAP), one of the inhibitors of apoptosis proteins (IAPs), is highly expressed and contributes to chemoresistance in AML. Hence, a novel drug, RO6867520 (RO‐BIR2), developed by Roche targeting the BIR2 domain in XIAP to reactivate blocked apoptosis, is a promising therapy for AML. The monotherapy of RO‐BIR2 had minimal effect on most of the AML cell lines tested except U‐937. In contrast to AML cell lines, in general, RO‐BIR2 alone has been shown to inhibit the proliferation of primary AML patient samples effectively and induced apoptosis in a dose‐dependent manner. A combination of RO‐BIR2 with TNF‐related apoptosis‐inducing ligand (TRAIL) led to highly synergistic effect on AML cell lines and AML patient samples. This combination therapy is capable of inducing apoptosis, thereby leading to an increase in specific apoptotic cell population, along with the activation of caspase 3/7. A number of apoptotic‐related proteins such as XIAP, cleavage of caspase 3, cleavage of caspase 7, and cleaved PARP were changed upon combination therapy. Combination of RO‐BIR2 with Ara‐C had similar effect as the TRAIL combination. Ara‐C combination also led to synergistic effect on AML cell lines and AML patient samples with low combination indexes (CIs). We conclude that the combination of RO‐BIR2 with either TRAIL or Ara‐C represents a potent therapeutic strategy for AML and is warranted for further clinical trials to validate the synergistic benefits in patients with AML, especially for the elderly who are abstaining from intensive chemotherapy.