Knockdown of miR-128a induces Lin28a expression and reverts myeloid differentiation blockage in acute myeloid leukemia

Abstract

Lin28A is a highly conserved RNA-binding protein that concurs to control the balance between stemness and differentiation in several tissue lineages. Here, we report the role of miR-128a/Lin28A axis in blocking cell differentiation in acute myeloid leukemia (AML), a genetically heterogeneous disease characterized by abnormally controlled proliferation of myeloid progenitor cells accompanied by partial or total inability to undergo terminal differentiation. First, we found Lin28A underexpressed in blast cells from AML patients and AML cell lines as compared with CD34+ normal precursors. In vitro transfection of Lin28A in NPM1-mutated OCI-AML3 cell line significantly triggered cell-cycle arrest and myeloid differentiation, with increased expression of macrophage associate genes (EGR2, ZFP36 and ANXA1). Furthermore, miR-128a, a negative regulator of Lin28A, was found overexpressed in AML cells compared with normal precursors, especially in acute promyelocytic leukemia (APL) and in ‘AML with maturation’ (according to 2016 WHO classification of myeloid neoplasms and acute leukemia). Its forced overexpression by lentiviral infection in OCI-AML3 downregulated Lin28A with ensuing repression of macrophage-oriented differentiation. Finally, knockdown of miR-128a in OCI-AML3 and in APL/AML leukemic cells (by transfection and lentiviral infection, respectively) induced myeloid cell differentiation and increased expression of Lin28A, EGR2, ZFP36 and ANXA1, reverting myeloid differentiation blockage. In conclusion, our findings revealed a new mechanism for AML differentiation blockage, suggesting new strategies for AML therapy based upon miR-128a inhibition.

Scutellaria barbata D. Don (SBD) protects oxygen glucose deprivation/reperfusion-induced injuries of PC12 cells by up-regulating Nrf2

“…Several lines of evidence have implicated that SBD exerts a strong activity of anti-tumour, anti-oxidative stress and anti-inflammation [10][11][12]. Recent studies mainly focused on its anti-tumour effects which have been reported in many kinds of cancers [13][14][15].…”

“…Scutellaria barbata D. Don (SBD), also known as Ban-Zhi-Lian, is a perennial herb with multiple pharmacological effects, including anti-inflammation, anti-oxidation and anti-tumour activity [10][11][12]. It has been demonstrated that SBD has a strong inhibitory effect on numerous human cancers, such as lung cancer, hepatocellular carcinoma and skin cancer [13][14][15].…”

MicroRNAs as New Biomarkers for Diagnosis and Prognosis, and as Potential Therapeutic Targets in Acute Myeloid Leukemia

“…Numerous studies demonstrated the existence of distinct miRNA profiles in different AML subtypes, indicating that miRNA signature contributed to AML heterogeneity, and suggesting its potential inclusion in clinical setting [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. In Table 1 were reported all major studies comparing miRNA profile between AML blasts and normal cells, and among AML with recurrent genetic abnormalities [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. Most of the reported studies exhibited high concordance in AML miRNA profile.…”

MicroRNA, an Antisense RNA, in Sensing Myeloid Malignancies

“…miR-181 and miR-128 target Lin28, leading to the progression of myeloid leukemia and differentiation blockage of hematopoietic cells to their lineage ( 15 , 70 , 71 ). The inhibition of miR-181 expression partially reverses the lack of myeloid differentiation in AML patients and in the mice implanted with CD34+ hematopoietic stem/progenitor cells (HSPCs) from AML patients ( 72 ).…”