“…Various SWI/SNF genes, such as ARID1A/1B/2 and SMARCA2/4 , are recurrently mutated across a wide variety of hematological and non-hematological cancers, whereas others, such as BCL7A , are specifically mutated in certain hematological malignancies [ 86 , 114 , 115 ]. Although the molecular mechanisms by which SWI/SNF mutations may promote such a wide variety of cancers remain largely unknown, two main models have been proposed (reviewed in [ 116 ]).…”
Section: Genetic Alterations Of Swi/snf Subunits In Hematological Mal...mentioning
confidence: 99%
“…Data sources: [ 7 , 8 , 82 , 83 ]. In the datasets of Reddy et al and Schmitz et al, previously missed splice site mutations from our previous reports have been added [ 86 , 115 ]. B Distribution of mutations in BCL7A, shown at the protein level.…”
Section: Genetic Alterations Of Swi/snf Subunits In Hematological Mal...mentioning
Hematological malignancies are a highly heterogeneous group of diseases with varied molecular and phenotypical characteristics. SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes play significant roles in the regulation of gene expression, being essential for processes such as cell maintenance and differentiation in hematopoietic stem cells. Furthermore, alterations in SWI/SNF complex subunits, especially in ARID1A/1B/2, SMARCA2/4, and BCL7A, are highly recurrent across a wide variety of lymphoid and myeloid malignancies. Most genetic alterations cause a loss of function of the subunit, suggesting a tumor suppressor role. However, SWI/SNF subunits can also be required for tumor maintenance or even play an oncogenic role in certain disease contexts. The recurrent alterations of SWI/SNF subunits highlight not only the biological relevance of SWI/SNF complexes in hematological malignancies but also their clinical potential. In particular, increasing evidence has shown that mutations in SWI/SNF complex subunits confer resistance to several antineoplastic agents routinely used for the treatment of hematological malignancies. Furthermore, mutations in SWI/SNF subunits often create synthetic lethality relationships with other SWI/SNF or non-SWI/SNF proteins that could be exploited therapeutically. In conclusion, SWI/SNF complexes are recurrently altered in hematological malignancies and some SWI/SNF subunits may be essential for tumor maintenance. These alterations, as well as their synthetic lethal relationships with SWI/SNF and non-SWI/SNF proteins, may be pharmacologically exploited for the treatment of diverse hematological cancers.
“…Various SWI/SNF genes, such as ARID1A/1B/2 and SMARCA2/4 , are recurrently mutated across a wide variety of hematological and non-hematological cancers, whereas others, such as BCL7A , are specifically mutated in certain hematological malignancies [ 86 , 114 , 115 ]. Although the molecular mechanisms by which SWI/SNF mutations may promote such a wide variety of cancers remain largely unknown, two main models have been proposed (reviewed in [ 116 ]).…”
Section: Genetic Alterations Of Swi/snf Subunits In Hematological Mal...mentioning
confidence: 99%
“…Data sources: [ 7 , 8 , 82 , 83 ]. In the datasets of Reddy et al and Schmitz et al, previously missed splice site mutations from our previous reports have been added [ 86 , 115 ]. B Distribution of mutations in BCL7A, shown at the protein level.…”
Section: Genetic Alterations Of Swi/snf Subunits In Hematological Mal...mentioning
Hematological malignancies are a highly heterogeneous group of diseases with varied molecular and phenotypical characteristics. SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes play significant roles in the regulation of gene expression, being essential for processes such as cell maintenance and differentiation in hematopoietic stem cells. Furthermore, alterations in SWI/SNF complex subunits, especially in ARID1A/1B/2, SMARCA2/4, and BCL7A, are highly recurrent across a wide variety of lymphoid and myeloid malignancies. Most genetic alterations cause a loss of function of the subunit, suggesting a tumor suppressor role. However, SWI/SNF subunits can also be required for tumor maintenance or even play an oncogenic role in certain disease contexts. The recurrent alterations of SWI/SNF subunits highlight not only the biological relevance of SWI/SNF complexes in hematological malignancies but also their clinical potential. In particular, increasing evidence has shown that mutations in SWI/SNF complex subunits confer resistance to several antineoplastic agents routinely used for the treatment of hematological malignancies. Furthermore, mutations in SWI/SNF subunits often create synthetic lethality relationships with other SWI/SNF or non-SWI/SNF proteins that could be exploited therapeutically. In conclusion, SWI/SNF complexes are recurrently altered in hematological malignancies and some SWI/SNF subunits may be essential for tumor maintenance. These alterations, as well as their synthetic lethal relationships with SWI/SNF and non-SWI/SNF proteins, may be pharmacologically exploited for the treatment of diverse hematological cancers.
“…B-cell lymphoma is a heterogeneous group of hematological malignancies originating from B cells and accounts for up to 35% of non-Hodgkin’s lymphomas. 6 , 27 DLBCL has a global annual incidence of more than 100,000 cases. As a result, identification of the cause, pathogenesis, prognosis, and presentation is critical for improving the diagnostic process, classification, outcome stratification, and personalized therapy.…”
Section: Splicing Mutation In Dlbcl Pathogenesismentioning
confidence: 99%
“… 27 , 30 Splicing mutations most commonly affect B-cell lymphoma 7 protein family member A (BCL7A), cluster of differentiation 79B (CD79B), myeloid differentiation primary response gene 88 (MYD88), tumor protein P53 (TP53), signal transducer and activator of transcription (STAT), serum- and glucose-regulated kinase 1 (SGK1), caspase recruitment domain-containing protein 11 (CARD11), zinc finger proteins 36L1 (ZFP36L1), PR domain zinc finger protein 1 (PRDM1), pou class 2 associating factor 1 (POU2AF1), and neurogenic locus notch homolog protein 1 (NOTCH1) ( Figure 4 ). 6 , 35 , 36 Figure 4 Schematic representation of pathological mechanisms DLBCL in splicing mutation. …”
Section: Splicing Mutation In Dlbcl Pathogenesismentioning
confidence: 99%
“…The BCL7A gene is located on chromosome 12 and is affected most commonly by a splicing mutation. 6 Its products play a role in B cell activation and tumor suppressor function. In the BCL7A gene, three different splicing site mutations, such as mutant splice site, cryptic splice site, and exon skipping, were found.…”
Section: Role Of Splice Site Mutation On Bcl7a Genementioning
Ribonucleic acid splicing is a crucial process to create a mature mRNA molecule by removing introns and ligating exons. This is a highly regulated process, but any alteration in splicing factors, splicing sites, or auxiliary components affects the final products of the gene. In diffuse large B-cell lymphoma, splicing mutations such as mutant splice sites, aberrant alternative splicing, exon skipping, and intron retention are detected. The alteration affects tumor suppression, DNA repair, cell cycle, cell differentiation, cell proliferation, and apoptosis. As a result, malignant transformation, cancer progression, and metastasis occurred in B cells at the germinal center. B-cell lymphoma 7 protein family member A (BCL7A), cluster of differentiation 79B (CD79B), myeloid differentiation primary response gene 88 (MYD88), tumor protein P53 (TP53), signal transducer and activator of transcription (STAT), serum- and glucose-regulated kinase 1 (SGK1), Pou class 2 associating factor 1 (POU2AF1), and neurogenic locus notch homolog protein 1 (NOTCH) are the most common genes affected by splicing mutations in diffuse large B cell lymphoma.
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