Splicing factor mutations in the myelodysplastic syndromes: target genes and therapeutic approaches

Armstrong, Richard N.; Steeples, Violetta; Singh, Shalini; Sanchi, Andrea; Boultwood, Jacqueline; Pellagatti, Andrea

doi:10.1016/j.jbior.2017.09.008

Cited by 22 publications

(39 citation statements)

References 196 publications

(344 reference statements)

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“…40 The presence of specific somatic mutations does not yet influence the decision to treat with HMAs. In general, it suggests more or less aggressive strategies (eg, earlier timing of HSCT for eligible patients carrying numerous mutations) and drives second-choice therapies when genes like IDH1/IDH2 41,42 or spliceosome components 42 are mutated, for which specific inhibitors 42,43 are available. The patient presented in case 1 had an ASXL1 mutation, among others, and transplantation seemed the best option.…”

Section: Response To Hmas and Somatic Mutationsmentioning

confidence: 99%

“…Spliceosome inhibitory agents Various spliceosome genes are frequently mutated in MDS. 43 Because of the good correlation between genotype/phenotype and prognostic significance, these altered genes constitute an ideal target for specific agents. Toxic consequences of inhibition of RNA splicing in the different tissues (mainly ocular toxicity) were clear from early studies of E7107 65 but are not present in the ongoing phase 1 study of H3B-8800 (#NCT02841540), 66 an orally bioavailable modulator of the SF3B complex administered to patients experiencing HMA failure and those with pretreated AML and MDS.…”

Section: Novel Hmasmentioning

confidence: 99%

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How I treat MDS after hypomethylating agent failure

Santini

2019

Blood

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Hypomethylating agents (HMA) azacitidine and decitabine are standard of care for myelodysplastic syndrome (MDS). Response to these agents occurs in ∼50% of treated patients, and duration of response, although variable, is transient. Prediction of response to HMAs is possible with clinical and molecular parameters, but alternative approved treatments are not available, and in the case of HMA failure, there are no standard therapeutic opportunities. It is important to develop a reasoned choice of therapy after HMA failure. This choice should be based on evaluation of type of resistance (primary vs secondary, progression of disease [acute leukemia or higher risk MDS] vs absence of hematological improvement) as well as on molecular and cytogenetic characteristics reassessed at the moment of HMA failure. Rescue strategies may include stem-cell transplantation, which remains the only curative option, and chemotherapy, both of which are feasible in only a minority of cases, and experimental agents. Patients experiencing HMA failure should be recruited to clinical experimental trials as often as possible. Several novel agents with different mechanisms of action are currently being tested in this setting. Drugs targeting molecular alterations (IDH2 mutations, spliceosome gene mutations) or altered signaling pathways (BCL2 inhibitors) seem to be the most promising.

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Section: Response To Hmas and Somatic Mutationsmentioning

confidence: 99%

Section: Novel Hmasmentioning

confidence: 99%

How I treat MDS after hypomethylating agent failure

Santini

2019

Blood

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“…Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic diseases characterized by ineffective hematopoiesis leading to peripheral blood cytopenias, and are likely to evolve into acute myelogenous leukemia (AML). [1][2][3] The prognosis of MDS is very diverse because of the background of their genetic heterogeneity. Common karyotypic abnormalities have been included in the Revised International Prognostic Scoring System (IPSS-R), 4 and the development of next-generation sequencing (NGS) has revealed that approximately 90% of MDS patients have a somatic mutation in at least one driver gene.…”

Section: Introductionmentioning

confidence: 99%

Prognostic significance of U2AF1 mutations in myelodysplastic syndromes: a meta-analysis

Zou

Yang

et al. 2019

J Int Med Res

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Introduction: Although the effects of U2 small nuclear RNA auxiliary factor 1 gene (U2AF1) mutations on the outcomes of patients with myelodysplastic syndromes (MDS) have previously been investigated, their prognostic significance remains controversial. We performed a metaanalysis to investigate the impact of U2AF1 mutations on MDS progression. Methods: Two reviewers independently extracted information such as hazard ratios (HRs) and 95% confidential intervals (CIs) for overall survival (OS) and leukemia-free survival (LFS) as well as the number of surviving patients each year after diagnosis from the included studies. Results: Thirteen studies with a total of 3038 patients were included. The summary odds ratio (OR) for U2AF1 mutations with an OS of 5 years was 0.37, the summary HR for U2AF1 mutations in OS was 1.60, and the summary OR for an OS of 5 years in patients with U2AF1 S34 and U2AF1 Q157 was 3.68. There were no significant differences in leukemia-free survival or hypomethylating therapy response between patients with and without U2AF1 mutations. Conclusion: U2AF1 mutations were associated with poor survival in MDS patients, and patients with U2AF1 Q157 had a worse OS than those with U2AF1 S34 . Our findings suggest that MDS patients with U2AF1 mutations could benefit more from hypomethylation therapy.

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“…The clinical efficacy of hypomethylating agents also suggests that epigenetic dysregulation is important in the molecular pathogenesis of MDS. In addition, cumulative evidences indicate importance of splicing factor gene mutations, which are most frequent mutations in MDS patients, in molecular pathogenesis of MDS . Mutations of splicing factor genes may affect global gene expression and splicing, resulting in alteration of expression level and/or splicing in diverse genes, which may include the PLCG1 gene, involved in molecular pathogenesis of MDS.…”

Section: Discussionmentioning

confidence: 99%

Reduced PLCG1 expression is associated with inferior survival for myelodysplastic syndromes

et al. 2019

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The PLCG1 gene, which encodes the phospholipase C γ1 isoform, is located within the commonly deleted region of the long arm of chromosome 20 (del(20q)) observed in myelodysplastic syndromes (MDS). Phospholipase C is involved in diverse physiological and pathological cellular processes through inositide signaling. We hypothesized that reduced PLCG1 expression because of haploinsufficiency by del(20q) plays a role in the molecular pathogenesis of MDS. Therefore, we analyzed PLCG1 expression in bone marrow mononuclear cells at diagnosis in 116 MDS patients with or without del(20q) by quantitative RT‐PCR to evaluate its clinical significance. The expression level of PLCG1 was significantly lower not only in MDS patients with del(20q) but also in those without del(20q) compared to that of the controls, which suggests that reduced PLCG1 expression is a common molecular event in MDS. Patients in the lowest quartile (Q4) group for PLCG1 expression had lower overall survival (OS) compared to that of other patients (Q1‐Q3) (log‐rank test, P = .0004) with estimated median OS times of 22 in the Q4 group and 106 months in the Q1‐3 group. Univariate and multivariate analysis indicated reduced PLCG1 expression (Q4) was associated with lower OS (hazard ratio 2.58, 95% CI 1.35‐4.84, P = .0049), which suggests that reduced PLCG1 expression is an independent prognostic factor for OS. In addition, patients were well‐stratified for OS by combining PLCG1 expression level (Q4 vs Q1‐3) and bone marrow blast percentage (5% or more vs less than 5%). Thus, the level of PLCG1 expression at time of diagnosis is a prognostic biomarker for MDS.

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Splicing factor mutations in the myelodysplastic syndromes: target genes and therapeutic approaches

Cited by 22 publications

References 196 publications

How I treat MDS after hypomethylating agent failure

How I treat MDS after hypomethylating agent failure

Prognostic significance of U2AF1 mutations in myelodysplastic syndromes: a meta-analysis

Reduced PLCG1 expression is associated with inferior survival for myelodysplastic syndromes

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