Functional dissection of inherited non-coding variation influencing multiple myeloma risk

Ajore, Ram; Niroula, Abhishek; Pertesi, Maroulio; Cafaro, Caterina; Thodberg, Malte; Went, Molly; Bao, Erik L.; Duran-Lozano, Laura; Portilla, Aitzkoa Lopez de Lapuente; Ugidos-Damboriena, Nerea; Magnusson, Olafur T; Samur, Mehmet K.; Lareau, Caleb A.; Halldorsson, Gisli H.; Þorleifsson, Guðmar; Norddahl, Gudmundur L.; Gunnarsdóttir, Kristbjörg; Försti, Asta; Goldschmidt, Hartmut; Hemminki, Kari; Rhee, Frits van; Kimber, Scott; Sperling, Adam S.; Kaiser, Martin; Anderson, Kenneth C.; Jónsdóttir, Ingileif; Munshi, Nikhil C.; Rafnar, Thorunn; Waage, Anders; Weinhold, Niels; Þorsteinsdóttir, Unnur; Sankaran, Vijay G.; Stefánsson, Kāri; Houlston, Richard S.; Nilsson, Björn

doi:10.1038/s41467-021-27666-x

Cited by 23 publications

(12 citation statements)

References 84 publications

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“…With our increasing understanding of the molecular mechanisms that guide normal B-cell differentiation, the possibilities to understand the functional consequences of these mutational landscapes in leukemia also increase. This extends beyond genetic aberrations in the coding genes, as the deconvolution of enhancer networks provides a better understanding of how mutations or polymorphisms in regulatory elements contribute to malignant transformation ( Mansour et al 2014 ; Yang et al 2020 ; Montefiori et al 2021 ; Ajore et al 2022 ). The increased knowledge regarding the basic principles of dynamic gene regulation, including transcriptional bursting ( Zhou and Murre 2021 ) and chromosome dynamics in B-lymphocyte development ( Lin et al 2012 ; Barajas-Mora et al 2023 ), may provide unique insights into the processes of cell differentiation and lineage commitment.…”

Section: Discussionmentioning

confidence: 99%

Transcription factor networks link B-lymphocyte development and malignant transformation in leukemia

Sigvardsson

2023

Genes Dev.

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Rapid advances in genomics have opened unprecedented possibilities to explore the mutational landscapes in malignant diseases, such as B-cell acute lymphoblastic leukemia (B-ALL). This disease is manifested as a severe defect in the production of normal blood cells due to the uncontrolled expansion of transformed B-lymphocyte progenitors in the bone marrow. Even though classical genetics identified translocations of transcription factor-coding genes in B-ALL, the extent of the targeting of regulatory networks in malignant transformation was not evident until the emergence of large-scale genomic analyses. There is now evidence that many B-ALL cases present with mutations in genes that encode transcription factors with critical roles in normal B-lymphocyte development. These includePAX5,IKZF1,EBF1, andTCF3, all of which are targeted by translocations or, more commonly, partial inactivation in cases of B-ALL. Even though there is support for the notion that germline polymorphisms in thePAX5andIKZF1genes predispose for B-ALL, the majority of leukemias present with somatic mutations in transcription factor-encoding genes. These genetic aberrations are often found in combination with mutations in genes that encode components of the pre-B-cell receptor or the IL-7/TSLP signaling pathways, all of which are important for early B-cell development. This review provides an overview of our current understanding of the molecular interplay that occurs between transcription factors and signaling events during normal and malignant B-lymphocyte development.

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Section: Discussionmentioning

confidence: 99%

Transcription factor networks link B-lymphocyte development and malignant transformation in leukemia

Sigvardsson

2023

Genes Dev.

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“…49 At present, SMARCD3 has been less deeply researched. Previous studies about SMARCD3 mainly focused on the function of SMARCD3 in phosphorylation, 50 gene-regulatory myeloma susceptibility, 51 chemotherapy-induced breast cancer stemness, 52 and heart development. 53 In this study, we found that SMARCD3 was downregulated by UCA1.…”

Section: Discussionmentioning

confidence: 99%

lncRNA UCA1 promotes tumor progression by targeting SMARCD3 in cervical cancer

An,

Dong,

Chi

et al. 2023

Molecular Carcinogenesis

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Long noncoding RNA urothelial carcinoma associated 1 (UCA1) has been identified as a key molecule in human cancers. However, its functional implications remain unspecified in the context of cervical cancer (CC). This research aims to identify the regulatory mechanism of UCA1 in CC. UCA1 was identified through microarray and confirmed through a quantitative real‐time polymerase chain reaction. Proteins that bind with UCA1 were recognized using RNA pull‐down assays along with RNA immunoprecipitation. Ubiquitination assays and coimmunoprecipitation were performed to explore the molecular mechanisms of the SWI/SNF‐related, matrix‐associated, actin‐dependent regulator of chromatin, subfamily d, member 3 (SMARCD3) downregulated in CC. The effects of UCA1 and SMARCD3 on the progression of CC were investigated through gain‐ and loss‐of‐function assays and xenograft tumor formation in vivo. In this study, UCA1 was found to be upregulated in CC cells as well as in human plasma exosomes for the first time. Functional studies indicated that UCA1 promotes CC progression. Mechanically, UCA1 downregulated the SMARCD3 protein stabilization by promoting SMARCD3 ubiquitination. Taken together, we revealed that the UCA1/SMARCD3 axis promoted CC progression, which could provide a new therapeutic target for CC.

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“…In tissue culture, its overexpression induces abnormally long centrioles, which are fragmented, incomplete, and asymmetric at their elongated distal ends, and contain supernumerary, randomly positioned subdistal appendages [ 6 ], highly reminiscent of our findings in plasma cells. Moreover, a non-coding variant upregulating plasma cell expression of CEP120, another CPAP-associated centriole elongation activator and appendage assembly factor [ 53 , 54 ], has recently been shown to increase MM susceptibility [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

High-throughput electron tomography identifies centriole over-elongation as an early event in plasma cell disorders

Köhrer,

Dittrich,

Schorb

et al. 2023

Leukemia

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Plasma cell disorders are clonal outgrowths of pre-malignant or malignant plasma cells, characterized by extensive chromosomal aberrations. Centrosome abnormalities are a major driver of chromosomal instability in cancer but their origin, incidence, and composition in primary tumor cells is poorly understood. Using cutting-edge, semi-automated high-throughput electron tomography, we characterized at nanoscale 1386 centrioles in CD138pos plasma cells from eight healthy donors and 21 patients with plasma cell disorders, and 722 centrioles from different control populations. In plasma cells from healthy individuals, over-elongated centrioles accumulated with age. In plasma cell disorders, centriole over-elongation was notably frequent in early, pre-malignant disease stages, became less pronounced in overt multiple myeloma, and almost entirely disappeared in aggressive plasma cell leukemia. Centrioles in other types of patient-derived B cell neoplasms showed no over-elongation. In contrast to current belief, centriole length appears to be highly variable in long-lived, healthy plasma cells, and over-elongation and structural aberrations are common in this cell type. Our data suggest that structural centrosome aberrations accumulate with age in healthy CD138pos plasma cells and may thus play an important role in early aneuploidization as an oncogenic driver in plasma cell disorders.

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Functional dissection of inherited non-coding variation influencing multiple myeloma risk

Cited by 23 publications

References 84 publications

Transcription factor networks link B-lymphocyte development and malignant transformation in leukemia

Transcription factor networks link B-lymphocyte development and malignant transformation in leukemia

lncRNA UCA1 promotes tumor progression by targeting SMARCD3 in cervical cancer

High-throughput electron tomography identifies centriole over-elongation as an early event in plasma cell disorders

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