Zhou J1,2, Bi C1, Ching YQ1, Chooi JY2, Lu X1, Quah JY1, Toh SH1, Chan ZL1, Tan TZ1, Chong PS1, Chng WJ3,4,5.
1 Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, Singapore, 117599, Republic of Singapore.
2 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074, Republic of Singapore.
3 Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, Singapore, 117599, Republic of Singapore. firstname.lastname@example.org.
4 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074, Republic of Singapore. email@example.com.
5 Department of Hematology-Oncology, National University Cancer institute of Singapore, The National University Health System (NUHS), 1E, Kent Ridge Road, Singapore, 119228, Republic of Singapore. firstname.lastname@example.org.
BACKGROUND: Current 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.
METHODS: We 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.
RESULTS: We 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.
CONCLUSIONS: In 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.
KEYWORDS: Acute myeloid leukemia (AML); Cancer metabolism; IGF2BP1; LIN28B; Stem cell; let-7 microRNA