Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia

Wang, Lili; Brooks, Angela N.; Fan, Jean; Wan, Yong; Gambe, Rutendo; Li, Shuqiang; Hergert, Sarah; Yin, Shanye; Freeman, Samuel S.; Levin, Joshua Z.; Lin, Fan; Seiler, Michael; Buonamici, Silvia; Smith, Peter G.; Chau, Kevin F.; Cibulskis, Carrie; Zhang, Wandi; Rassenti, Laura Z.; Ghia, Emanuela M.; Kipps, Thomas J.; Fernandes, Stacey M.; Bloch, Donald B.; Kotliar, Dylan; Landau, Dan A.; Shukla, Sachet A.; Aster, Jon C.; Reed, Robin; DeLuca, David S.; Brown, Jennifer R.; Neuberg, Donna; Getz, Gad; Livak, Kenneth J.; Meyerson, Matthew; Kharchenko, Peter V.; Wu, Catherine J.

doi:10.1016/j.ccell.2016.10.005

Cited by 176 publications

(203 citation statements)

References 45 publications

(65 reference statements)

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“…12,15,34,35 U2AF1 mutations alter exon inclusion/exclusion in a sequence-specific manner, 3,10 and last, loss of function mutations in ZRSR2 specifically affects assembly of the minor spliceosome.…”

Section: Introductionmentioning

confidence: 99%

How do messenger RNA splicing alterations drive myelodysplasia?

Joshi

Halene

Abdel-Wahab

2017

Blood

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Mutations in RNA splicing factors are the single most common class of genetic alterations in myelodysplastic syndrome (MDS) patients. Although much has been learned about how these mutations affect splicing at a global-and transcript-specific level, critical questions about the role of these mutations in MDS development and maintenance remain. Here we present the questions to be addressed in order to understand the unique enrichment of these mutations in MDS. (Blood. 2017; 129(18):2465-2470 IntroductionMyelodysplastic syndromes (MDSs) represent clonal disorders of hematopoietic stem cells (HSCs) whereby hematopoietic cell-intrinsic genetic alterations as well as non-cell autonomous factors contribute to an aberrant HSC that produces morphologically abnormal progeny and has impaired ability to generate mature blood cells. Due to the wide clinical and morphologic heterogeneity of MDS, substantial effort has been placed on characterizing the genetic alterations present in MDS cells in hopes of improving our ability to understand, diagnose, and treat the disease. Extensive targeted mutational analysis of protein coding genes has identified that MDS is characterized by a high frequency of mutations in genes encoding messenger RNA (mRNA) splicing factors as well as epigenetic modifiers.1-3 The discovery of mutations in RNA splicing factors in particular was quite unexpected as these mutations are generally uncommon in cancer yet are present in 50% to 60% of MDS patients. Interestingly, there are clear associations between specific mutated splicing factors and subtypes of MDS, most notably mutations in the RNA splicing factor SF3B1 in .90% of patients with MDS with ring sideroblasts.1,2,4 Moreover, the nature of these mutations is quite conspicuous as they occur as heterozygous point mutations at highly recurrent residues. Finally, within MDS patients, these mutations are almost always mutually exclusive; an MDS patient almost never has .1 RNA splicing factor mutation at the same time [1][2][3] (although rare individuals with mutations in .1 RNA splicing factor have been noted, 5 these occur far less frequently than expected by chance in MDS and it is unclear if both mutations in such cases are present within the same cell and/or how the mutations may impact splicing if coexpressed in the same cell).The discovery of RNA splicing factor mutations has led to intense efforts to understand their biological impact on hematopoiesis, 6-9 their genomic and biochemical effects on RNA splicing, 10-21 their structural effects, 22 and potential means to therapeutically target cells bearing these mutations. 8,[23][24][25] Although there have been major advances in understanding the role of RNA splicing factor mutations in MDS pathogenesis and therapy (as reviewed recently [26][27][28] ), major questions about their biological consequences within cells, requirement in disease initiation vs maintenance, and cell autonomous vs nonautonomous roles remain. In addition, numerous questions about the structural and biochemical effects of...

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Section: Introductionmentioning

confidence: 99%

How do messenger RNA splicing alterations drive myelodysplasia?

Joshi

Halene

Abdel-Wahab

2017

Blood

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“…Heterozygous missense mutations of the C-terminal HEAT domain are the most frequent alteration to SF3B1, impacting spliceosomal function (17). Indeed, SF3B1 mutation has been shown to induce large numbers of aberrantly spliced and altered gene products in CLL (18). The frequency of SF3B1 mutations and the resulting changes to spliceosomal activity suggest that dysregulation of the spliceosome plays a prominent role in CLL pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Proteomics Profiling of CLL Versus Healthy B-cells Identifies Putative Therapeutic Targets and a Subtype-independent Signature of Spliceosome Dysregulation

Johnston

Carter

Larráyoz

et al. 2018

Molecular & Cellular Proteomics

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“…The role of SF3B1 mutations at the cellular level remains unknown [67]. Possibly, modified product of the mutated gene interacts incorrectly with RNA and cofactors.…”

Section: Sf3b1mentioning

confidence: 99%

“…The recent studies suggest that the mutation results in anomaly of the response to the DNA damage what disturbs genomic stability [65,66]. Other cellular functions that might be deregulated are telomere maintenance and NOTCH signaling in CLL cells [67].…”

Section: Sf3b1mentioning

confidence: 99%

Novel prognostic molecular factors: a quantum leap in the field of chronic lymphocytic leukemia

Zakrzewska

Piróg

Purkot

et al. 2017

Folia Histochem Cytobiol.

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Cytogenetic lesions do not completely explain clinical heterogeneity of chronic lymphocytic leukemia (CLL). The 2016 revision of the World Health Organization classification 2008 indicated that molecular lesions of TP53, NOTCH1, SF3B1 and BIRC3 have potential clinical relevance and could be integrated into an updated risk profile. The negative clinical implications of TP53 disruptions are well constituted and patients with these mutations should be considered for novel, small molecule signal transduction inhibitors therapies. Mutations of NOTCH1, SF3B1 and BIRC3 are associated with poor prognosis. Patients with mutated SF3B1 or NOTCH1 genes present shorter time to first treatment compared to unmutated group. NOTCH1 mutations are related to a high risk of Richter's syndrome transformation, especially in case of TP53 disruptions' coexistence. Large studies on MYD88 mutations in CLL have not explained clearly their clinical importance. The aim of this paper is to provide a comprehensive review on novel molecular aberrations identified in CLL.

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Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia

Cited by 176 publications

References 45 publications

How do messenger RNA splicing alterations drive myelodysplasia?

How do messenger RNA splicing alterations drive myelodysplasia?

Proteomics Profiling of CLL Versus Healthy B-cells Identifies Putative Therapeutic Targets and a Subtype-independent Signature of Spliceosome Dysregulation

Novel prognostic molecular factors: a quantum leap in the field of chronic lymphocytic leukemia

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