Abnormal expression of ADAR1 isoforms in Chinese pediatric acute leukemias

Ma, Chao; Chong, Jing-Hui; Guo, Ye; Zeng, Huimin; Liu, Shuyan; Xu, Lvjie; Wei, Jia; Yang, Lin; Zhu, Xiaofan; Zheng, Guoguang

doi:10.1016/j.bbrc.2011.02.025

Cited by 20 publications

(20 citation statements)

References 23 publications

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“…A previous study demonstrated that ADAR1 was among the top 5% of genes expressed in the mutational evolution of lobular breast cancer (36), indicating that activation of ADARs may correlate with disease progression in multiple malignant cell types (31). Although previous studies have shown ADAR1 p110 up-regulation in a murine leukemia model (42) and in pediatric acute leukemias (43), it should be emphasized that human hematopoietic tissues undergo dramatic changes during aging (44,45) that are caused in part by increased inflammation and genomic instability (46).…”

Section: Discussionmentioning

confidence: 92%

ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia

Jiang

Crews

Barrett

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

157

194

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The molecular etiology of human progenitor reprogramming into self-renewing leukemia stem cells (LSC) has remained elusive. Although DNA sequencing has uncovered spliceosome gene mutations that promote alternative splicing and portend leukemic transformation, isoform diversity also may be generated by RNA editing mediated by adenosine deaminase acting on RNA (ADAR) enzymes that regulate stem cell maintenance. In this study, wholetranscriptome sequencing of normal, chronic phase, and serially transplantable blast crisis chronic myeloid leukemia (CML) progenitors revealed increased IFN-γ pathway gene expression in concert with BCR-ABL amplification, enhanced expression of the IFN-responsive ADAR1 p150 isoform, and a propensity for increased adenosine-to-inosine RNA editing during CML progression. Lentiviral overexpression experiments demonstrate that ADAR1 p150 promotes expression of the myeloid transcription factor PU.1 and induces malignant reprogramming of myeloid progenitors. Moreover, enforced ADAR1 p150 expression was associated with production of a misspliced form of GSK3β implicated in LSC self-renewal. Finally, functional serial transplantation and shRNA studies demonstrate that ADAR1 knockdown impaired in vivo self-renewal capacity of blast crisis CML progenitors. Together these data provide a compelling rationale for developing ADAR1-based LSC detection and eradication strategies.

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Section: Discussionmentioning

confidence: 92%

ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia

Jiang

Crews

Barrett

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

157

194

View full text Add to dashboard Cite

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“…It should be noted that an opposite role for ADAR1-P150 was reported in HeLa cells (42) and that these differences might be due to cell-specific miRNA and target gene expression profiles. In addition, an upregulation of ADAR1 was observed in some other malignancies, such as lobular breast cancer (43) and B cell acute lymphoblastic leukemia (44).The robust dominance of ADAR1-P110 probably dictates the final cellular outcome. The corroboration between the robust cell regulatory roles of ADAR1 with its common low expression in melanoma metastasis strongly points to a central involvement of ADAR1 in melanoma progression.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth

et al. 2013

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Some solid tumors have reduced posttranscriptional RNA editing by adenosine deaminase acting on RNA (ADAR) enzymes, but the functional significance of this alteration has been unclear. Here, we found the primary RNA-editing enzyme ADAR1 is frequently reduced in metastatic melanomas. In situ analysis of melanoma samples using progression tissue microarrays indicated a substantial downregulation of ADAR1 during the metastatic transition. Further, ADAR1 knockdown altered cell morphology, promoted in vitro proliferation, and markedly enhanced the tumorigenicity in vivo. A comparative whole genome expression microarray analysis revealed that ADAR1 controls the expression of more than 100 microRNAs (miRNAs) that regulate many genes associated with the observed phenotypes. Importantly, we discovered that ADAR1 fundamentally regulates miRNA processing in an RNA binding-dependent, yet RNA editing-independent manner by regulating Dicer expression at the translational level via let-7. In addition, ADAR1 formed a complex with DGCR8 that was mutually exclusive with the DGCR8-Drosha complex that processes pri-miRNAs in the nucleus. We found that cancer cells silence ADAR1 by overexpressing miR-17 and miR-432, which both directly target the ADAR1 transcript. We further demonstrated that the genes encoding miR-17 and miR-432 are frequently amplified in melanoma and that aberrant hypomethylation of the imprinted DLK1-DIO3 region in chromosome 14 can also drive miR-432 overexpression.

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“…The qRT-PCR primers for p150 or p110 (depicted as numbers 1 and 2 in Supplementary Fig. 1A) were designed as described (Ma et al [15]); the p150 qRT-PCR products contained the first start codon (AUG1), whereas the p110 qRT-PCR products spanned exon 1B and exon 2. We also introduced another pair of primers (designed for the p150 and p110 transcripts, depicted as number 7 in Supplementary Fig.…”

Section: Differential Expression Patterns Of Adar1 In Glioma Tissues mentioning

confidence: 99%

“…Disrupted RNA editing levels or abnormal ADAR expression is associated with many diseases, such as cancer. In recent years, several studies have revealed the relationship between ADAR and malignant tumors, mainly in leukemia and glioblastoma (GBM) [15][16][17][18][19][20]. Over-expressed ADAR2 (also known as ADARB1) can inhibit glioma proliferation and the cell cycle through CDC-14B editing [19]; however, the expression and biological role of ADAR1 in gliomas remain unclear.…”

Section: Introductionmentioning

confidence: 99%

PTBP1 induces ADAR1 p110 isoform expression through IRES-like dependent translation control and influences cell proliferation in gliomas

Yang

Lin

et al. 2015

Cell. Mol. Life Sci.

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Internal ribosomal entry site (IRES)-mediated translation initiation is constitutively activated during stress conditions such as tumorigenesis and hypoxia. The RNA editing enzyme ADAR1 plays an important role in physiology and pathology. Initially, we found that the ADAR1 p150 or p110 transcript levels were decreased in glioma cells compared with normal astrocyte cells. In contrast, protein levels of ADAR1 p110 were significantly upregulated in glioma tissues and cells. This expression pattern indicated translationally controlled regulation. We identified an 885-nt sequence that was located between AUG1 and AUG2 within the ADAR1 mRNA that exhibited IRES-like activity. Furthermore, we confirmed that the translational mode of ADAR1 p110 was mediated by PTBP1 in glioma cells. The protein levels of PTBP1 and ADAR1 were cooperatively expressed in glioma tissues and cells. Knocking down ADAR1 p110 significantly decreased cell proliferation in three types of glioma cells (T98G, U87MG and A172). The removal of a minimal IRES-like sequence in a p150-overexpression construct could effectively abolish p110 induction and resulted in the slight suppression of cell proliferation compared with ADAR1-p150 overexpression in siPTBP1-treated T98G cells. In summary, our study revealed a mechanism whereby ADAR1 p110 can be activated by PTBP1 through an IRES-like element in glioma cells, and ADAR1 is essential for the maintenance of gliomagenesis.

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Abnormal expression of ADAR1 isoforms in Chinese pediatric acute leukemias

Cited by 20 publications

References 23 publications

ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia

ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia

MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth

PTBP1 induces ADAR1 p110 isoform expression through IRES-like dependent translation control and influences cell proliferation in gliomas

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