Implications of the miR-10 family in chemotherapy response of NPM1-mutated AML

Abstract

• High miR-10 family expression levels in AML patients are associated with achieving complete remission to induction chemotherapy.• Functional experiments did not show any impact of miR10a-5p in AML blast growth or survival at baseline conditions or after chemotherapy.Nucleophosmin-mutated acute myeloid leukemia (NPM1mut-AML) patients have a high rate of complete remission (CR) to induction chemotherapy. However, the mechanisms responsible for such effects are unknown. Because miR-10 family members are expressed at high levels in NPM1mut-AML, we evaluated whether these microRNAs could predict chemotherapy response in AML. We found that high baseline miR-10 family expression in 54 untreated cytogenetically heterogeneous AML patients was associated with achieving CR. However, when we included NPM1 mutation status in the multivariable model, there was a significant interaction effect between miR-10a-5p expression and NPM1 mutation status. Similar results were observed when using a second cohort of 183 cytogenetically normal older (age ‡ 60 years) AML patients. Loss-and gain-of-function experiments using miR-10a-5p in cell lines and primary blasts did not demonstrate any effect in apoptosis or cell proliferation at baseline or after chemotherapy. These data support a bystander role for the miR-10 family in NPM1mut-AML. (Blood. 2014;123(15):2412-2415 IntroductionMutations of the nucleophosmin (NPM1) gene, usually occurring at exon 12, represent the most common genetic alteration in cytogenetically normal acute myeloid leukemia (CN-AML) (50% to 60% of cases) and account for about one-third of all adult AML. 1-3 The presence of NPM1 mutations is associated with high complete remission (CR) rates in young and elderly AML patients (70% to 85%). [1][2][3] However, the mechanisms responsible for such an effect on chemotherapy response are unknown. Unraveling those mechanisms will be critical to understand why NPM1 mutations are associated with high CR and may provide novel targets for therapeutic development.MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by repressing or promoting translation and/or accelerating messenger RNA decay. 4 MiRNA expression is dysregulated in AML blasts 5 and is associated with specific cytogenetic and molecular alterations. [5][6][7][8] It has been shown that a unique miRNA signature is associated with CN-AML patients harboring NPM1 mutations and includes the strong upregulation of miR-10a-5p and miR-10b-5p. 7,8 However, the functional role of these 2 miRNAs in NPM1-mutated AML (NPM1mut-AML) is unknown. Here, we asked whether the miR-10 family could predict chemotherapy response in AML and whether the chemotherapy sensitivity and high CR rates observed in NPM1mut-AML patients could be mediated through miR-10 family members. To answer these questions, we analyzed miR-10 family expression in relation to CR and NPM1 mutation status in 2 cohorts of de novo AML patients. Furthermore, we performed miR-10a-5p gain-and loss-of-function studies using AML cell lines and primar...

Serum level of miR-10-5p as a prognostic biomarker for acute myeloid leukemia

“…Higher levels of miR10a-5p expression in AML compared to normal control and down-regulation of miR-10a-5p expression in CML patients with respect to healthy donor [27] implicated that miR-10a-5p may play a crucial role in mediating the differentiation of myeloid lineage. Previous report showed that no differences in CD11b or cell morphology were observed up to 72 h after miR-10a-5p overexpression in Kasumi-1 cells [30]. However, to date, minimal evidence exists to indicate that microRNAs which were involved in the differentiation block of M1 blasts and consequently monocytic differentiation differentially expressed between the M1 and M5 French-American-British (FAB) subtypes [31,32].…”

“…Previous published research has highlighted that miR-10a-5p was significantly markedly overexpressed and influenced the chemotherapy response in NPM1 mut AML, which may exert its biological properties in AML by interfering with the p53 machinery, which is partly regulated by MDM4 [13,14,30]. Certain research suggested that nuclear factor-κB (NF-κB) p65 activated miR-10a-5p expression by directly combining miR-10a-5p promoter region in human breast cancer and colorectal cancer cell lines [37].…”

Molecular and cellular aspects of extramedullary manifestations of acute myeloid leukemia

“…[60] High expression level of miR-10 family is associated with AML with mutated NPM-1. [25,61] Furthermore, miR-424 in AML patients with NPM-1 mutation was down-modulated. [62] In AML patients with the FLT3-ITD mutation, miR-451 and miR-144 were down-regulated while miR-155 was overexpressed.…”

Drug resistance-related microRNAs in hematological malignancies: Translating basic evidence into therapeutic strategies

“…miRNAs therefore represent a new set of particularly attractive therapeutic targets in overcoming MDR in hematological malignancies. In addition, differential miRNA Blood Reviews 29 (2015) [33][34][35][36][37][38][39][40][41][42][43][44] expression profiles in serum or plasma samples can be used as noninvasive diagnostic or prognostic biomarkers. Studies on miRNAs have therefore quickly moved from research on the molecular basis of cancer to clinical applications.…”