A novel <i>KMT2A–USO1</i> fusion gene‐induced <i>de novo</i> secondary acute myeloid leukaemia in a patient initially diagnosed with acute promyelocytic leukaemia

Wen, Ji; Chen, Li; Liu, Yabin; Chen, Qiusheng; Zhao, Ming; Tan, Yun; Zhang, Wei; Song, Huan; Weng, Xiang‐Qin; Mi, Jian-Qing; Chen, Sai‐Juan; Chen, Zhu; Li, Junmin; Wang, Kankan

doi:10.1111/bjh.17183

Cited by 2 publications

(3 citation statements)

References 10 publications

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“…Here, we focused on USO1 , based on its identification in this screen as well as a prior study in MV-4–11 AML cells that had identified USO1 as a factor required for AML survival 17 . A recent study reported a KMT2A(MLL)-USO1 fusion gene in a secondary AML, hinting at a further connection between MLL -driven leukemia and USO1 39 . More generally, USO1 has been shown to be of functional importance in cancer 23 – 25 .…”

Section: Discussionmentioning

confidence: 98%

Focused CRISPR-Cas9 genetic screening reveals USO1 as a vulnerability in B-cell acute lymphoblastic leukemia

Jaiswal

Truong

Tran

et al. 2021

Sci Rep

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Post-transcriptional gene regulation, including that by RNA binding proteins (RBPs), has recently been described as an important mechanism in cancer. We had previously identified a set of RBPs that were highly dysregulated in B-cell acute lymphoblastic leukemia (B-ALL) with MLL translocations, which carry a poor prognosis. Here, we sought to functionally characterize these dysregulated RBP genes by performing a focused CRISPR dropout screen in B-ALL cell lines, finding dependencies on several genes including EIF3E, EPRS and USO1. Validating our findings, CRISPR/Cas9-mediated disruption of USO1 in MLL-translocated B-ALL cells reduced cell growth, promoted cell death, and altered the cell cycle. Transcriptomic analysis of USO1-deficient cells revealed alterations in pathways related to mTOR signaling, RNA metabolism, and targets of MYC. In addition, USO1-regulated genes from these experimental samples were significantly and concordantly correlated with USO1 expression in primary samples collected from B-ALL patients. Lastly, we found that loss of Uso1 inhibited colony formation of MLL-transformed in primary bone marrow cells from Cas9-EGFP mice. Together, our findings demonstrate an approach to performing focused sub-genomic CRISPR screens and highlight a putative RBP vulnerability in MLL-translocated B-ALL, thus identifying potential therapeutic targets in this disease.

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Section: Discussionmentioning

confidence: 98%

Focused CRISPR-Cas9 genetic screening reveals USO1 as a vulnerability in B-cell acute lymphoblastic leukemia

Jaiswal

Truong

Tran

et al. 2021

Sci Rep

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“…In our study, a novel USO1 transcript variant containing exon 15 but lacking exon 5 was found in OSCC cells. Some studies have reported that USO1 is involved in the tumorigenesis of certain human malignant tumors [28][29][30][31]. For example, USO1 knockdown inhibits cell proliferation and induces cell apoptosis in multiple myeloma cells [28].…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, we discovered that Lsm12 plays key roles in the tumorigenesis of OSCC and can modulate alternative splicing of USO1 gene. USO1 has been identified as a tumor-related gene [28][29][30][31]. But the underlying molecular mechanism of USO1 gene in the tumorigenesis remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Identification of RNA-splicing factor Lsm12 as a novel tumor-associated gene and a potent biomarker in Oral Squamous Cell Carcinoma (OSCC)

Yan

Xue

Zhang

et al. 2022

J Exp Clin Cancer Res

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Background Oral squamous cell carcinoma (OSCC) is one of the common cancers worldwide. The lack of specific biomarkers and therapeutic targets leads to delayed diagnosis and hence the poor prognosis of OSCC patients. Thus, it is urgent to identify effective biomarkers and therapeutic targets for OSCC. Methods We established the golden hamster carcinogenic model of OSCC induced by 7,12-dimethylbenz(a) anthrancene (DMBA) and used mRNA microarrays to detect the differentially expressed genes (DEGs). DEGs were validated in OSCC clinical tissue microarrays using immunohistochemistry method. Whole transcriptome sequencing was performed to obtain an overview of biological functions of Lsm12. PCR assay and sequencing were employed to investigate the alternative splicing of genes regulated by Lsm12. Cell proliferation, colony formation, Transwell migration and invasion assay and in vivo tumor formation assay were performed to investigate the roles of Lsm12 and two transcript variants of USO1 in OSCC cells. Results Lsm12 was identified to be significantly up-regulated in the animal model of OSCC tumorigenesis, which was validated in the clinical OSCC samples. In the paired normal tissues, Lsm12 staining was negative (91%, 92/101) or weak, while in OSCC tissues, positive rate is 100% and strong staining spread over the whole tissues in 93 (93/101, 92%) cases. Lsm12 overexpression significantly promoted OSCC cell growth, colony formation, migration and invasion abilities, while Lsm12 knockdown showed the opposite trends on these phenotypes and obviously inhibited the tumor formation in vivo. Furthermore, Lsm12 overexpression caused the inclusion of USO1 exon 15 and Lsm12 knockdown induced exon 15 skipping. Exon 15-retained USO1 significantly promoted the malignant phenotypes of OSCC cells when compared with the exon 15-deleted USO1. Conclusions We identified Lsm12, a novel tumorigenesis-related gene, as an important regulator involved in OSCC tumorigenesis. Lsm12 is a novel RNA-splicing related gene and can regulate the alternative splicing of USO1 exon 15 which was associated closely with OSCC carcinogenesis. Our findings thus provide that Lsm12 might be a potent biomarker and potential therapeutic target for OSCC.

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A novel KMT2A–USO1 fusion gene‐induced de novo secondary acute myeloid leukaemia in a patient initially diagnosed with acute promyelocytic leukaemia

Cited by 2 publications

References 10 publications

Focused CRISPR-Cas9 genetic screening reveals USO1 as a vulnerability in B-cell acute lymphoblastic leukemia

Focused CRISPR-Cas9 genetic screening reveals USO1 as a vulnerability in B-cell acute lymphoblastic leukemia

Identification of RNA-splicing factor Lsm12 as a novel tumor-associated gene and a potent biomarker in Oral Squamous Cell Carcinoma (OSCC)

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