DIS3: The Enigmatic Gene in Multiple Myeloma

Ohguchi, Yasuyo; Ohguchi, Hiroto

doi:10.3390/ijms24044079

Cited by 9 publications

(8 citation statements)

References 64 publications

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“…In addition to TET2 and NRAS, other mutated genes in the patient appeared to be indirectly associated with the development of BPDCN or MF. It has been reported that loss of function in DIS3 increases the RAS protein level in multiple myeloma cells, which promotes the development of cancer cells (44). CSMD1 is a tumor suppressor gene, and dysregulation of CSMD1 can drive the NF-κB pathway and promote tumor progression (45).…”

Section: Discussionmentioning

confidence: 99%

Simultaneous blastic plasmacytoid dendritic cell neoplasm and myelofibrosis: A case report

Luo,

Li,

et al. 2024

Oncol Lett

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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare and aggressive tumor with an unknown pathogenesis. Myelofibrosis (MF) is a type of myeloproliferative neoplasm. MF can be secondary to several hematological malignancies, including chronic myeloid leukemia, myelodysplastic syndrome and hairy cell leukemia. In the present report, a rare case of BPDCN secondary to MF is described. A 70-year-old male patient developed a large purplish-red rash with recurrent symptoms. BPDCN was confirmed by immunohistochemistry of a biopsy specimen and flow cytometry of bone marrow cells. Bone marrow histopathology revealed MF. Next-generation sequencing of peripheral blood revealed mutations in the Tet methylcytosine dioxygenase 2 and NRAS proto-oncogene GTPase genes. The patient underwent one cycle of chemoimmunotherapy, but the condition progressed, an infection developed and the patient eventually died. The present case suggests that BPDCN can occur in conjunction with MF and that the prognosis of such patients is poor. Pathological examination and genetic testing aided in the diagnosis and treatment. This case emphasizes the need to raise awareness of BPDCN among clinicians and to be alert to the potential for fatal infection in patients with BPDCN combined with MF following myelosuppression triggered during chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Simultaneous blastic plasmacytoid dendritic cell neoplasm and myelofibrosis: A case report

Luo,

Li,

et al. 2024

Oncol Lett

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“…Controlled degradation of unnecessary RNA transcripts by the DIS3 family is essential for cell division and mitosis in eukaryotic cells. During the posttranscriptional regulation of gene expression, DIS3 family members are involved in the degradation of dispensable RNAs via their highly conserved 3′–5′ exoribonucleolytic activity 223 , 224 . The DIS3 family comprises three homologs, DIS3, DIS3L, and DIS3L2, in humans 225 , 226 .…”

Section: Dis3 3′–5′ Exoribonuclease Familymentioning

confidence: 99%

“…The two tandem CSDs and the C-terminal S1 domain confer substrate RNA binding. The PIN domain is located in the N-terminus of DIS3 and DIS3L but not DIS3L2, which endows DIS3 and DIS3L with endonucleolytic activity and tethers DIS3 and/or DIS3L to the nine-subunit core (EXO9) in the RNA exosome complex 224 . DIS3L is also known to have defective endonuclease activity because of the alteration of two essential catalytic residues within its PIN domain.…”

Section: Dis3 3′–5′ Exoribonuclease Familymentioning

confidence: 99%

“…Specifically, in MM, an extremely serious hematological malignancy, DIS3 was identified as one of the most significantly mutated genes, which also included K-Ras, N-Ras, p53, BRAF, TRAF3, and FAM46C. DIS3 mutations and altered expression have been reported in approximately 10% of patients with MM 223 , 224 , 233 . More strikingly, deletions of another posttranscriptional modulator, FAM46C, a noncanonical poly(A) polymerase, have been observed in ~20% of MM patients 234 .…”

Section: Dis3 3′–5′ Exoribonuclease Familymentioning

confidence: 99%

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RNA-binding proteins and exoribonucleases modulating miRNA in cancer: the enemy within

Seo,

Rhim,

Kim

2024

Exp Mol Med

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Recent progress in the investigation of microRNA (miRNA) biogenesis and the miRNA processing machinery has revealed previously unknown roles of posttranscriptional regulation in gene expression. The molecular mechanistic interplay between miRNAs and their regulatory factors, RNA-binding proteins (RBPs) and exoribonucleases, has been revealed to play a critical role in tumorigenesis. Moreover, recent studies have shown that the proliferation of hepatocellular carcinoma (HCC)-causing hepatitis C virus (HCV) is also characterized by close crosstalk of a multitude of host RBPs and exoribonucleases with miR-122 and its RNA genome, suggesting the importance of the mechanistic interplay among these factors during the proliferation of HCV. This review primarily aims to comprehensively describe the well-established roles and discuss the recently discovered understanding of miRNA regulators, RBPs and exoribonucleases, in relation to various cancers and the proliferation of a representative cancer-causing RNA virus, HCV. These have also opened the door to the emerging potential for treating cancers as well as HCV infection by targeting miRNAs or their respective cellular modulators.

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“…Deletions of chromosomal fragments, like del(13q), are also frequently observed, especially in non-HRD MM 8 . However, their role in disease progression is less well-defined 9,10 . Mutations or chromosomal abnormalities detected at the MGUS stage are considered primary events involved in tumor development.…”

Section: Introductionmentioning

confidence: 99%

Somatic DIS3 mutations in Multiple Myeloma arise early in clonal evolution, but are later counterselected due to toxicity

Kuliński,

Gewartowska,

Mroczek

et al. 2023

Preprint

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DIS3 encoding the essential catalytic subunit of the nuclear exosome complex degrading RNA in the nucleus is specifically mutated in multiple myeloma (MM). The impact of somatic driver DIS3 mutations on disease course is poorly understood. Clinical data analysis revealed that 42% of DIS3 mutations occur at three recurrent residues (D479, D488, and R780), and these mutations are never homozygous, often representing minor subclones in advanced MM. We further demonstrate a loss-of-heterozygosity of recurrent DIS3 alleles correlating with frequent del(13q) encompassing DIS3. Overexpression of the wild-type DIS3 increases the growth and viability of DIS3-mutated MM cell lines. In mice, heterozygous DIS3 D479 mutation leads to early embryonic lethality, confirming its dominant toxic effects. Transcriptome analysis of patients and cell lines reveals specific transcriptional signatures of DIS3 mutations, which are reversible upon DIS3 loss-of-heterozygosity. Early DIS3 alleles during MM clonal evolution create vulnerabilities that lead to their elimination under selective pressure.

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DIS3: The Enigmatic Gene in Multiple Myeloma

Cited by 9 publications

References 64 publications

Simultaneous blastic plasmacytoid dendritic cell neoplasm and myelofibrosis: A case report

Simultaneous blastic plasmacytoid dendritic cell neoplasm and myelofibrosis: A case report

RNA-binding proteins and exoribonucleases modulating miRNA in cancer: the enemy within

Somatic DIS3 mutations in Multiple Myeloma arise early in clonal evolution, but are later counterselected due to toxicity

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