Spliceosome-related gene mutations in myelodysplastic syndrome can be used as stable markers for monitoring minimal residual disease during follow-up

Matsuda, Kazuyuki; Ishida, Fumihiro; Ito, Toshiro; Nakazawa, Hayakazu; Miura, Shuhei; Taira, Chiaki; Sueki, Akane; Kobayashi, Yukihiro; Honda, Takayuki

doi:10.1016/j.leukres.2012.07.019

Cited by 6 publications

(4 citation statements)

References 41 publications

(58 reference statements)

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“…37,38 Also, allele-specific PCR have been designed, and these could be useful for monitoring minimal residual disease in MDS. 39 In summary, this study confirms that RARS-T should be considered an independent entity. In RARS-T patients, age o80 years at diagnosis, SF3B1 and JAK2 mutations are independent factors for better survival and may be used to stratify patients.…”

Section: Discussionsupporting

confidence: 78%

Age, JAK2V617F and SF3B1 mutations are the main predicting factors for survival in refractory anaemia with ring sideroblasts and marked thrombocytosis

et al. 2013

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Refractory anaemia with ring sideroblasts (RARS) and marked thrombocytosis (RARS-T) is a provisional entity in the World Health Organisation 2008 classification and has previously been shown to have a high proportion of JAK2(V617F) (Janus Kinase 2) and SF3B1 (Splicing Factor 3B subunit 1) mutations. The purpose of the present study was to analyse the frequency of SF3B1 mutations in a large cohort of 111 patients with RARS-T and 33 patients with RARS and to explore the prognostic impact of SF3B1 mutational status on RARS-T. The frequency of SF3B1 mutations in RARS-T (96/111, 86.5%) and RARS (28/33, 84.8%) was similar. In RARS-T, median survival was better in SF3B1-mutated patients than in SF3B1-non-mutated patients (6.9 and 3.3 years, respectively, P=0.003). RARS can be differentiated from RARS-T by the frequency of JAK2(V617F) (0% vs 48.6%). In RARS-T patients, SF3B1 (P=0.021) and JAK2 mutations (P=0.016) were independent factors for a better prognosis. Altogether, our results confirm that RARS-T is an independent entity that should be recognised by the next World Health Organisation classification. The assessment of SF3B1 mutations is of prognostic interest in RARS-T patients. Younger age, JAK2(V617F) and SF3B1 mutations are the main predicting factors for survival in RARS-T.

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Section: Discussionsupporting

confidence: 78%

Age, JAK2V617F and SF3B1 mutations are the main predicting factors for survival in refractory anaemia with ring sideroblasts and marked thrombocytosis

et al. 2013

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“…It is now well accepted that mutations affecting mRNA spicing machinery are likely to be early/initiating events in disease evolution and are present in virtually all malignant cells. The presence of point mutations as detected by PCR may also serve as a molecular marker of MRD after chemotherapy or hematopoietic stem cell transplant [79, 80, 83]. …”

Section: Markers Of Clonal Hematopoiesis In the Diagnosis And Prognosmentioning

confidence: 99%

I Walk the Line: How to Tell MDS From Other Bone Marrow Failure Conditions

Gondek

DeZern

2014

Curr Hematol Malig Rep

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Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by peripheral cytopenias and ineffective hematopoiesis. MDS is an example of an age-related malignancy and its increasing prevalence and incidence can be attributed to a greater life expectancy in developed countries. Although frequently encountered in hematology/oncology clinics, MDS may constitute a diagnostic challenge especially with equivocal bone marrow morphology. Certain syndromes of bone marrow failure (BMF) may mimic MDS and formulating a correct diagnosis is vital for adequate prognostication as well as therapeutic approaches. Metaphase karyotyping (MK) is a very important diagnostic tool and marker of prognosis and can be an indicator of response to certain therapies. Unfortunately chromosomal abnormalities may only be found in approximately 50% of patients with MDS. In this review, we discuss the diagnostic approaches to patients with pancytopenia with a particular focus on the growing number of somatic mutations through new molecular testing.

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“…Srsf2 is associated with a negative prognostic impact, as patients bearing mutations in Srsf2 have significantly inferior overall survival and a more rapid and frequent progression to acute myeloid leukemia (42,43). Depending on the disease classification and how the statistical analysis was performed and applied, Sf3b1, important for anchoring the spliceosome to precursor mRNA, has been proposed to serve either as a favorable marker in MDS or as an independent prognostic factor for progression (44,45). These findings suggest that imbalances in the spliceosome machinery can have a significant role in promoting leukemogenesis.…”

Section: Fig 3 Gene Ontology Of Nuclear Pi-plc␤1b Complex Biologicamentioning

confidence: 99%

Phosphoinositide-specific Phospholipase C β 1b (PI-PLCβ1b) Interactome: Affinity Purification-Mass Spectrometry Analysis of PI-PLCβ1b with Nuclear Protein

Piazzi

Blalock

Bavelloni

et al. 2013

Molecular & Cellular Proteomics

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Two isoforms of inositide-dependent phospholipase C ␤1 (PI-PLC␤1) are generated by alternative splicing (PLC␤1a and PLC␤1b). Both isoforms are present within the nucleus, but in contrast to PLC␤1a, the vast majority of PLC␤1b is nuclear. In mouse erythroid leukemia cells, PI-PLC␤1 is involved in the regulation of cell division and the balance between cell proliferation and differentiation. It has been demonstrated that nuclear localization is crucial for the enzymatic function of PI-PLC␤1, although the mechanism by which this nuclear import occurs has never been fully characterized. The aim of this study was to characterize both the mechanism of nuclear localization and the molecular function of nuclear PI-PLC␤1 by identifying its interactome in Friend's erythroleukemia isolated nuclei, utilizing a procedure that coupled immuno-affinity purification with tandem mass spectrometry analysis. Using this procedure, 160 proteins were demonstrated to be in association with PI-PLC␤1b, some of which have been previously characterized, such as the splicing factor SRp20 (Srsf3) and Lamin B (Lmnb1). Co-immunoprecipitation analysis of selected proteins confirmed the data obtained via mass spectrometry. Of particular interest was the identification of the nuclear import proteins Kpna2, Kpna4, Kpnb1, Ran, and Rangap1, as well as factors involved in hematological malignancies and several anti-apoptotic proteins. These data give new insight into possible mechanisms of nuclear trafficking and functioning of this critical signaling molecule. Molecular & Cellular Proteomics 12: 10.1074/ mcp.M113.029686, 2220-2235, 2013.1 is one of two existing isoforms of PI-PLC␤1produced by alternative splicing (1). PI-PLC␤1a (150 kDa) and PI-PLC␤1b (140 kDa) differ only at their carboxyl termini; PI-PLC␤1b is 43 amino acids shorter than PI-PLC␤1a. Both isoforms present with a non-canonical nuclear localization signal comprising a cluster of lysine residues (2). In murine erythroleukemia (MEL) cells, both isoforms are present within the nucleus; however, in contrast to PI-PLC␤1a, PI-PLC␤1b is almost exclusively nuclear. Nuclear PI-PLC␤1 is known to be involved in specific signal transduction pathways that differ from those occurring in other cellular compartments. The role of PI-PLC␤1 has been extensively studied in the nucleus, and PI-PLC␤1 is now considered a key co-factor for several nuclear processes, including cell growth, proliferation, and differentiation.In MEL cells, PI-PLC␤1 is involved in regulating G1/S (3) and G2/M (4) cell cycle progression. During G1/S transition, overexpression of PI-PLC␤1 results in up-regulation of the cyclin D3/cdk4 complex. This complex is responsible for the phosphorylation of retinoblastoma protein and the subsequent activation of the E2F-1 transcription factor, forcing cells out of the G1 phase of the cell cycle. In G2/M, the production of inositol-3-phosphate and diacylglycerol (DAG) from the cleavage of phosphatidylinositol-4,5-bisphosphate results in PKC␣-dependent phosphorylation of lamin B, leading to n...

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Spliceosome-related gene mutations in myelodysplastic syndrome can be used as stable markers for monitoring minimal residual disease during follow-up

Cited by 6 publications

References 41 publications

Age, JAK2V617F and SF3B1 mutations are the main predicting factors for survival in refractory anaemia with ring sideroblasts and marked thrombocytosis

Age, JAK2V617F and SF3B1 mutations are the main predicting factors for survival in refractory anaemia with ring sideroblasts and marked thrombocytosis

I Walk the Line: How to Tell MDS From Other Bone Marrow Failure Conditions

Phosphoinositide-specific Phospholipase C β 1b (PI-PLCβ1b) Interactome: Affinity Purification-Mass Spectrometry Analysis of PI-PLCβ1b with Nuclear Protein

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