Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo

Shirai, Cara Lunn; Ley, James N; White, Brian S.; Kim, Sanghyun P.; Tibbitts, Justin; Shao, Jin; Ndonwi, Matthew; Wadugu, Brian A.; Duncavage, Eric J.; Okeyo-Owuor, Theresa; Liu, Tuoen; Griffith, Malachi; McGrath, Sean; Magrini, Vincent; Fulton, Robert S.; Fronick, Catrina C.; O’Laughlin, Michelle; Graubert, Timothy A.; Walter, Matthew J.

doi:10.1016/j.ccell.2015.04.008

Cited by 263 publications

(347 citation statements)

References 54 publications

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“…To confirm that somatic gene mutations prime HSPCs for pyroptosis in MDSs, we performed comparative analyses of published gene expression profiles from human and murine SRSF2 (GSE65349) and U2AF1 mutants (GSE30195 and GSE66793) vs WT, TET2 knockout (GSE27816), and primary MDS (GSE19429) vs normal HSPCs and found uniform upregulation of pyroptosis effectors, consistent with transcriptional priming. [39][40][41][42][43] Importantly, in MDS BM specimens, BM plasma concentration of S100A9 positively correlated with NLRP3 MFI, percentage and MFI of plasma ASC specks, and the presence of SGMs and variant allele frequency (supplemental Figure 8). Furthermore, both the percentage and MFI of plasma ASC specks were significantly increased in MDS patients harboring SGMs (supplemental Figure 8D-E).…”

Section: Org Frommentioning

confidence: 90%

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

Basiorka¹,

McGraw²,

Eksioglu³

et al. 2016

Blood

295

350

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Key Points• Key biological features of MDSs are explained by NLRP3 inflammasome activation, which drives pyroptotic cell death and b-catenin activation.• Alarmin signals and founder gene mutations license this redox-sensitive inflammasome platform.Despite genetic heterogeneity, myelodysplastic syndromes (MDSs) share features of cytological dysplasia and ineffective hematopoiesis. We report that a hallmark of MDSs is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins and manifest activated NLRP3 complexes that direct activation of caspase-1, generation of interleukin-1b (IL-1b) and IL-18, and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPCs and bone marrow plasma. Further, like somatic gene mutations, S100A9-induced signaling activates NADPH oxidase (NOX), increasing levels of reactive oxygen species (ROS) that initiate cation influx, cell swelling, and b-catenin activation. Notably, knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROS generation, and nuclear b-catenin in MDSs and are sufficient to restore effective hematopoiesis. Thus, alarmins and founder gene mutations in MDSs license a common redox-sensitive inflammasome circuit, which suggests new avenues for therapeutic intervention. (Blood. 2016;128(25):2960-2975

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Section: Org Frommentioning

confidence: 90%

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

Basiorka¹,

McGraw²,

Eksioglu³

et al. 2016

Blood

295

350

View full text Add to dashboard Cite

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“…17 The study population was selected on the basis of the availability of sufficient DNA and was not otherwise biased by any other selection criteria. Targeted capture assays were carried out on bone marrow or whole blood DNA for the following genes: TET2 (exons 3, 9, 10, and 11), DNMT3A (exons 4,8,13,15,16,18,19,20,22, and 23), IDH1 (exon 4), IDH2 (exon 4), ASXL1 (exon 12), EZH2 (exons 8, 17, and 18), SUZ12 (all exons), SRSF2 (exon 1), SF3B1 (exons 13, 15, and 17), ZRSR2 (all exons), U2AF1 (exons 2 and 6), PTPN11 (all exons), TP53 (exons 5, 6, 7, and 8), SH2B3 (all exons), RUNX1 (exons 3, 4, and 8), CBL (exons 8 and 9), NRAS (exons 2 and 3), JAK2 (exons 12 and 14), CSF3R (exons 14 and 17), FLT3 (exons 14 and 20), KIT (all exons), CALR (all exons), MPL (exon 10), NPM1 (exon 11), CEBPA (exon 1), IKZF1 (all exons), and SETBP1 (exon 3).…”

Section: Methodsmentioning

confidence: 99%

Targeted deep sequencing in primary myelofibrosis

Tefferi¹,

Lasho²,

Finke³

et al. 2016

Blood Advances

194

202

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Key Points• More than 80% of patients with PMF harbor DNA variants/mutations other than JAK2/ CALR/MPL.• Some of these variants/mutations adversely affect overall or leukemia-free survival independent of conventional risk stratification.A myeloid neoplasm-relevant 27-gene panel was used for next-generation sequencing of bone marrow or whole blood DNA in 182 patients with primary myelofibrosis (PMF). DNA sequence variants/mutations other than JAK2/CALR/MPL were detected in 147 patients (81%), with the most frequent being ASXL1 (36%), TET2 (18%), SRSF2 (18%), and U2AF1(16%); furthermore, 35%, 26%, 10%, and 9% of the patients harbored 1, 2, 3, or 4 or more such variants/mutations, respectively. Adverse variants/mutations were identified by ageadjusted multivariable analysis of impact on overall survival or leukemia-free survival and included ASXL1, SRSF2, CBL, KIT, RUNX1, SH2B3, and CEBPA; their combined prevalence was 56%. Adverse variants/mutations were associated with inferior overall survival (median, 3.6 vs 8.5 years; P , .001) and leukemia-free survival (7-year risk, 25% vs 4%; P , .001), and the effect on survival was independent of both the Dynamic International Prognostic Scoring System Plus and JAK2/CALR/MPL mutational status, with respective hazard ratios of 2.0 (95% confidence interval [CI], 1.3-3.1) and 2.9 (95% CI, 1.9-4.4).Additional prognostic information was obtained by considering the number of adverse variants/mutations; median survivals in patients with zero (n 5 80), 1 or 2 (n 5 93), or 3 or more (n 5 9) adverse variants/mutations were 8.5, 4, and 0.7 years, respectively (P , .001).Additional data were obtained on pattern of mutation co-segregation and phenotypic correlation, including significant associations between U2AF1 and JAK2 mutations (P 5 .04) and U2AF1 mutations and anemia (P 5 .003) and thrombocytopenia (P 5 .006). We conclude that DNA variants/mutations other than JAK2/CALR/MPL are prevalent in PMF and are qualitatively and quantitatively relevant in predicting overall and leukemia-free survival.

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“…57,59 Further insights into the functional consequences of splicing factor gene mutations have been gained through in vivo modeling of the U2AF1 hotspot mutation in a transgenic mouse model, which altered hematopoiesis associated with changes in pre-mRNA splicing of genes that are recurrent mutation targets in MDS and AML including BCOR and KMT2D (MLL2). 60 A recent complementary study focusing on SRSF2 showed that the mutation impairs hematopoietic differentiation in vivo. SRSF2 mutation was found to alter the binding specificity of SRSF2 to splice recognition motifs leading to missplicing of targets such as EZH2, thereby explaining the mutual exclusivity of EZH2 and SRSF2 mutations in myeloid malignancy.…”

Section: Splicing Factor Gene Mutationsmentioning

confidence: 99%

Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance

Grimwade

Ivey

Huntly

2016

Blood

375

300

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Recent major advances in understanding the molecular basis of acute myeloid leukemia (AML) provide a double-edged sword. Although defining the topology and key features of the molecular landscape are fundamental to development of novel treatment approaches and provide opportunities for greater individualization of therapy, confirmation of the genetic complexity presents a huge challenge to successful translation into routine clinical practice. It is now clear that many genes are recurrently mutated in AML; moreover, individual leukemias harbor multiple mutations and are potentially composed of subclones with differing mutational composition, rendering each patient’s AML genetically unique. In order to make sense of the overwhelming mutational data and capitalize on this clinically, it is important to identify (1) critical AML-defining molecular abnormalities that distinguish biological disease entities; (2) mutations, typically arising in subclones, that may influence prognosis but are unlikely to be ideal therapeutic targets; (3) mutations associated with preleukemic clones; and (4) mutations that have been robustly shown to confer independent prognostic information or are therapeutically relevant. The reward of identifying AML-defining molecular lesions present in all leukemic populations (including subclones) has been exemplified by acute promyelocytic leukemia, where successful targeting of the underlying PML-RARα oncoprotein has eliminated the need for chemotherapy for disease cure. Despite the molecular heterogeneity and recognizing that treatment options for other forms of AML are limited, this review will consider the scope for using novel molecular information to improve diagnosis, identify subsets of patients eligible for targeted therapies, refine outcome prediction, and track treatment response.

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Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo

Cited by 263 publications

References 54 publications

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

Targeted deep sequencing in primary myelofibrosis

Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance

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