<i>MIR142</i> Loss-of-Function Mutations Derepress ASH1L to Increase <i>HOXA</i> Gene Expression and Promote Leukemogenesis

Trissal, Maria; Wong, Terrence N.; Yao, Juo‐Chin; Ramaswamy, Rahul; Kuo, Iris; Baty, Jack; Sun, Yaping; Jih, Gloria; Parikh, Nishi; Berrien-Elliott, Melissa M.; Fehniger, Todd A.; Ley, Timothy J.; Maillard, Ivan; Reddy, Pavan; Link, Daniel C.

doi:10.1158/0008-5472.can-17-3592

Cited by 45 publications

(69 citation statements)

References 49 publications

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“…As there is no list of previously defined miRNA driver genes, we could not formally validate our approach; however, among the top-scored overmutated miRNA genes, we identified hsa-miR-142, which is the only miRNA gene in which mutations were identified in several hematologic neoplasms in several studies [49][50][51][52][53]56,57 , and their cancer relevance was functionally confirmed 27 . Our analysis confirmed the recurrence of hsa-miR-142 mutations in hematologic neoplasms, i.e., LAML, DLBC, and also the newly identified mutation in the Burkitt lymphoma Raji cell line, but also showed mutations in several solid tumors, i.e., UCEC, BLCA, GBM, and BRCA.…”

Section: Discussionmentioning

confidence: 99%

“…This result may suggest that the miRNA hairpin precursor is quite a fragile structure, and therefore, almost any mutation may be deleterious for the gene, either by disturbing the structure of the precursor or by disruption of the seed sequence. A recent functional study of two seed mutations, i.e., chr17:58331264T>C[-] and chr17:58331261C>G[-], showed that even though the mutations are located in miR-142-3p, they result in a decrease in both miR-142-3p and miR-142-5p levels and reverse the miR-5p:3p ratio (in favor of miR-3p) 27 . The functional consequences of the mutations are (i) aberration of hematopoietic differentiation, enhancing the myeloid and suppressing the lymphoid potential of hematopoietic progenitors, and (ii) inefficient repression of ASH1L, resulting in increased levels of HOXA9 and A10 (positively regulated by ASH1L) and ultimately leukemic transformation 27 .…”

Section: Hsa-mir-142mentioning

confidence: 99%

“…A recent functional study of two seed mutations, i.e., chr17:58331264T>C[-] and chr17:58331261C>G[-], showed that even though the mutations are located in miR-142-3p, they result in a decrease in both miR-142-3p and miR-142-5p levels and reverse the miR-5p:3p ratio (in favor of miR-3p) 27 . The functional consequences of the mutations are (i) aberration of hematopoietic differentiation, enhancing the myeloid and suppressing the lymphoid potential of hematopoietic progenitors, and (ii) inefficient repression of ASH1L, resulting in increased levels of HOXA9 and A10 (positively regulated by ASH1L) and ultimately leukemic transformation 27 . Although the effects of other mutations were not directly tested, it is likely that they are also deleterious mutations, resulting in similar functional consequences to the two functionally validated mutations.…”

Section: Hsa-mir-142mentioning

confidence: 99%

“…Despite the scarcity of identified miRNA gene mutations, the individual examples of SNPs, germline or somatic mutations provide proof, at least for some of the scenarios listed above. Examples include (i) the mutation in the seed sequence of miR-204-5p, affecting target recognition, that causes inherited retinal dystrophy 20 ; (ii) the mutation in the passenger strand of hsa-miR-96 that destabilizes the structure of the miRNA precursor, affects its processing, and decreases the miR-96-5p level, eventually resulting in the same phenotypic effect as mutations in the seed sequence of the guide strand, i.e., nonsyndromic inherited hearing loss 21,22 ; (iii) the G>C substitution (SNP rs138166791) in the penultimate position of the 3p passenger strand of hsa-miR-890 that significantly lowers the cleavage efficiency by DROSHA and consequently decreases the levels of both mature miR-890-5p and passenger miR-890-3p 23 ; (iv) the G>C substitution (SNP rs2910164) located in the 3p passenger strand of hsa-miR-146a that is associated with an increased risk of papillary thyroid carcinoma, where it was shown that the C allele of the SNP alters the structure of the precursor, decreases expression of the mature miRNA and activates the passenger strand, which becomes the second mature miRNA modulating many genes involved in the regulation of apoptosis 24 ; (v) interesting example is a mutation in the seed sequence of miR-184-3p, causing familial keratoconus, whose effect is not the disruption of miR-184-3p target recognition but the inability to mask overlapping targets for miR-205 in INPPL1 and ITGB4 25 ; (vi) mutations in hsa-miR-30c-1 and hsa-miR-17 that affect the precursor structure and thereby increase the levels of mature miRNAs, downregulating BRCA1 in familial breast cancer cases without BRCA1/2 mutations 26 ; and finally, (vii) two different somatic mutations in the seed sequence of miR-142-3p, found in acute myeloid leukemia (AML) samples, that were shown to decrease both miR-142-5p and miR-142-3p levels and reverse the miR-5p/3p ratio (in favor of miR-3p) 27 (more details and references on mutations in hsa-miR-142 in the subsequent sections). An additional indication of miRNA gene sensitivity to genetic alteration is their general high conservation and the decreased density of common SNPs in miRNA hairpin sequences [28][29][30] , which resembles the commonly known phenomenon of the decreased level of nonsynonymous SNPs in protein-coding sequences.…”

Section: Introductionmentioning

confidence: 99%

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Pan-Cancer analysis of somatic mutations in miRNA genes

Urbanek-Trzeciak

Galka-Marciniak

Nawrocka

et al. 2020

Preprint

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175)miRNAs are considered important players in oncogenesis, serving either as oncomiRs or suppressormiRs. Although the accumulation of somatic alterations is an intrinsic aspect of cancer development and many important cancer-driving mutations have been identified in protein-coding genes, the area of functional somatic mutations in miRNA genes is heavily understudied. Here, based on analysis of the whole-exome sequencing of over 10,000 cancer/normal sample pairs deposited within the TCGA repository, we identified and characterized over 10,000 somatic mutations in miRNA genes and showed that some of the genes are overmutated in Pan-Cancer and/or specific cancers. Nonrandom occurrence of the identified mutations was confirmed by a strong association of overmutated miRNA genes with KEGG pathways, most of which were related to specific cancer types or cancer-related processes. Additionally, we showed that mutations in some of the overmutated genes correlate with miRNA expression, cancer staging, and patient survival. Our results may also be the first step (form the basis and provide the resources) in the development of computational and/or statistical approaches/tools dedicated to the identification of cancerdriver miRNA genes. The results published here are based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. This work was supported by research grants from the Polish National Science Centre [2016/22/A/NZ2/00184 (to P.K.) and 2015/17/N/NZ3/03629 (to M.O.U-T.)] Authors contributions MUTparticipated in conceiving the study, wrote all the scripts, performed most of the computational and statistical analyses, drafted the manuscript, prepared figures, tables, and supplementary materials; PGMparticipated in conceiving the study, discussed the study on all steps of analyses, participated in manuscript preparation, performed some analyses (3D structures); PNdiscussed the analyses on all steps of the study, performed some analyses, participated in manuscript preparation; EKperformed the sequencing experiments, critically read and corrected manuscript; SSperformed the sequencing experiments, critically read and corrected manuscript; MGprovided samples for the hsa-miR-1324 and hsa-miR-142 sequencing validation experiments, advised on hematological neoplasms and head and neck cancer, critically read and corrected manuscript; PKreceived financing, participated in conceiving the study, supervised and coordinated the study, drafted the manuscript (with MUT).

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Section: Discussionmentioning

confidence: 99%

Section: Hsa-mir-142mentioning

confidence: 99%

Section: Hsa-mir-142mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pan-Cancer analysis of somatic mutations in miRNA genes

Urbanek-Trzeciak

Galka-Marciniak

Nawrocka

et al. 2020

Preprint

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“…A recent study indicated that miR-142-5p functioned to suppress cell migration by targeting VCAM-1 in bone marrow-derived mesenchymal stem cells [40]. Trisaal et al showed that loss-of-function the in miR-142 gene resulted in the increase in HOXA gene (a key gene for maintaining stemness in hematopoietic stem cells) and promoted leukemogenesis [41]. Together, the results from others and this study have provided evidence for the role of miR-142-5p as a tumor suppressor, while the decreased level of miR-142-5p was linked to the EMT and stemness of ESCC.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Cancer Metabolic SREBP1/miR-142-5p Suppresses Epithelial–Mesenchymal Transition and Stemness in Esophageal Carcinoma

Huang

Hsu

et al. 2019

Cells

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Elevated activity of sterol regulatory element-binding protein 1 (SREBP1) has been implicated in the tumorigenesis of different cancer types. However, the functional roles of SREBP1 in esophageal cancer are not well appreciated. Here, we aimed to investigate the therapeutic potential of SREBP1 and associated signaling in esophageal cancer. Our initial bioinformatics analyses showed that SREBP1 expression was overexpressed in esophageal tumors and correlated with a significantly lower overall survival rate in patients. Additionally, tumor suppressor miR-142-5p was predicted to target SREBP1/ZEB1 and a lower miR-142-5p was correlated with poor prognosis. We then performed in vitro experiments and showed that overexpressing SREBP1 in OE33 cell line led to increased abilities of colony formation, migration, and invasion; the opposite was observed in SREBP1-silenced OE21cells and SREBP1-silencing was accompanied by the reduced mesenchymal markers, including vimentin (Vim) and ZEB1, while E-cadherin and tumor suppressor miR-142-5p were increased. Subsequently, we first demonstrated that both SREBP1 and ZEB1 were potential targets of miR-142-5p, followed by the examination of the regulatory circuit of miR-142-5p and SREBP1/ZEB1. We observed that increased miR-142-5p level led to the reduced tumorigenic properties, such as migration and tumor sphere formation, and both observations were accompanied by the reduction of ZEB1 and SREBP1, and increase of E-cadherin. We then explored the potential therapeutic agent targeting SREBP1-associated signaling by testing fatostatin (4-hydroxytamoxifen, an active metabolite of tamoxifen). We found that fatostatin suppressed the cell viability of OE21 and OE33 cells and tumor spheres. Interestingly, fatostatin treatment reduced CD133+ population in both OE21 and OE33 cells in concert of increased miR-142-5p level. Finally, we evaluated the efficacy of fatostatin using a xenograft mouse model. Mice treated with fatostatin showed a significantly lower tumor burden and better survival rate as compared to their control counterparts. The treatment of fatostatin resulted in the reduced staining of SREBP1, ZEB1, and Vim, while E-cadherin and miR-142-5p were increased. In summary, we showed that increased SREBP1 and reduced miR-142-5p were associated with increased tumorigenic properties of esophageal cancer cells and poor prognosis. Cells 2020, 9, 7 2 of 15Preclinical tests showed that suppression of SREBP1 using fatostatin led to the reduced malignant phenotype of esophageal cancer via the reduction of EMT markers and increased tumor suppressor, miR-142-5p. Further investigation is warranted for the clinical use of fatostatin for the treatment of esophageal malignancy.

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microRNA expression in acute myeloid leukaemia: New targets for therapy?

Fletcher

Brown

Javadala

et al. 2022

eJHaem

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Recent studies have shown that short non-coding RNAs, known as microRNAs (miR-NAs) and their dysregulation, are implicated in the pathogenesis of acute myeloid leukaemia (AML). This is due to their role in the control of gene expression in a variety of molecular pathways. Therapies involving miRNA suppression and replacement have been developed. The normalisation of expression and the subsequent impact on AML cells have been investigated for some miRNAs, demonstrating their potential to act as therapeutic targets. Focussing on miRs with therapeutic potential, we have reviewed those that have a significant impact on the aberrant biological processes associated with AML, and crucially, impact leukaemic stem cell survival. We describe six miRNAs in preclinical trials (miR-21, miR-29b, miR-126, miR-181a, miR-223 and miR-196b) and two miRNAs that are in clinical trials (miR-29 and miR-155). However none have been used to treat AML patients and greater efforts are needed to develop miRNA therapies that could benefit AML patients in the future.

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MIR142 Loss-of-Function Mutations Derepress ASH1L to Increase HOXA Gene Expression and Promote Leukemogenesis

Cited by 45 publications

References 49 publications

Pan-Cancer analysis of somatic mutations in miRNA genes

Pan-Cancer analysis of somatic mutations in miRNA genes

Disruption of Cancer Metabolic SREBP1/miR-142-5p Suppresses Epithelial–Mesenchymal Transition and Stemness in Esophageal Carcinoma

microRNA expression in acute myeloid leukaemia: New targets for therapy?

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