SF3B1 mutations in myelodysplastic syndromes: clinical associations and prognostic implications

Damm, Frédérik; Thol, Felicitas; Kosmider, Olivier; Kade, Sofia; Löffeld, Patrick; Dreyfus, François; Stamatoullas‐Bastard, Aspasia; Tanguy‐Schmidt, Aline; Beyne‐Rauzy, Odile; Botton, Stéphane de; Guerci‐Bresler, Agnès; Göhring, Gudrun; Schlegelberger, Brigitte; Ganser, Arnold; Bernard, Olivier A.; Fontenay, Michaëla; Heuser, Michael

doi:10.1038/leu.2011.321

Cited by 80 publications

(86 citation statements)

References 15 publications

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“…This may be relevant to the observation that mutations are associated with poorer overall survival in CLL, 2,3,6 wheres in the myelodysplastic syndrome (MDS) they correlate with a more favorable disease subtype and improved survival even though the strikingly similar distribution of mutations suggest similar mechanisms of action. 10,[18][19][20] It was previously demonstrated that chemo-refractory CLL is enriched for SF3B1 mutations (17%) compared with 4% at diagnosis. 6 In contrast, we observed a similar high frequency (17%) in previously untreated patients and no correlation between the presence of a mutation and response to treatment.…”

Section: Discussionmentioning

confidence: 99%

The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial

Oscier

Rose-Zerilli

Winkelmann

et al. 2013

Blood

193

189

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Key Points• This is the first study to validate the importance of NOTCH1 and SF3B1 gene mutations in the context of a randomized, prospective clinical trial.• Mutations in both genes are independent prognostic biomarkers, and therefore have clinical utility in the accurate risk-adapted stratification of CLL patients. Continuing Medical Education onlineThis activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and the American Society of Hematology. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s) ™ . Physicians should claim only the credit commensurate with the extent of their participationin the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at http://www.medscape.org/journal/blood; and (4) view/print certificate. For CME questions, see page 566. Disclosures Associate Editor John G. Gribben served as an advisor or consultant for Celgene and Roche and as a speaker or a member of a speakers bureau for Roche, Jensen, and Celgene. The authors and CME questions author Laurie Barclay, freelance writer and reviewer, Medscape, LLC, declare no competing financial interests. For personal use only. on May 9, 2018. by guest www.bloodjournal.org From Continuing Medical Education online Learning objectivesUpon completion of this activity, participants will be able to:1. Describe the frequency of NOTCH1 and SF3B1 mutations in patients with chronic lymphocytic leukemia (CLL), and their correlations with other genetic markers.2. Describe survival in CLL patients with NOTCH1 mutations, and the prognostic value of this mutation. 3. Describe survival in CLL patients with SF3B1 mutations, and the prognostic value of this mutation.

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Section: Discussionmentioning

confidence: 99%

The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial

Oscier

Rose-Zerilli

Winkelmann

et al. 2013

Blood

193

189

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“…It is estimated that >90% of human genes undergo alternative splicing and translate into various protein isoforms for different functions, so this splicing process is important for gene expression diversity [12,13]. The clinical implications of mutations involving some of these splicing machinery genes, like SRSF2 [8,11,[14][15][16][17][18] and SF3B1 [8,9,11,14,[19][20][21][22], in MDS patients have been explored. U2AF1 (synonym U2AF35), another splicing machinery gene frequently mutated in MDS [8,10,15,16], belongs to the splicing factor SR family genes and encodes the small subunit of U2 auxiliary factor complex required for the binding of U2 snRNP to the pre-mRNA branch site [23,24].…”

Section: Introductionmentioning

confidence: 99%

Clinical implications of U2AF1 mutation in patients with myelodysplastic syndrome and its stability during disease progression

Tang

Lin

et al. 2013

American J Hematol

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We aimed to analyze clinical impacts of the U2AF1 mutation on patients with myelodysplastic syndrome (MDS) and its stability during disease progression. We checked mutation status of the U2AF1 by direct sequencing in 478 de novo MDS patients and correlated with the clinical characteristics and outcomes. We also sequentially analyzed the U2AF1 mutation in 421 samples from 142 patients to determine its stability during the disease courses. Thirty-six patients (7.5%) were found to have U2AF1 mutations, which occurred more frequently in younger patients (P 5 0.033). U2AF1 mutation was an independent poor-risk factor for overall survival (OS) in all patients (P 5 0.030) and younger patients (P 5 0.041). U2AF1 mutation could also predict shorter time-to-leukemia transformation (TTL) in younger patients (P 5 0.020). In addition, U2AF1 mutation was associated with shorter TTL in lower-risk MDS patients. Sequential analyses showed all original U2AF1 mutations in U2AF1-mutated patients were retained during follow-ups unless complete remission was achieved, whereas none of the U2AF1-wild patients acquired a novel mutation during disease evolution. U2AF1 mutation is more prevalent in younger MDS patients and associated with inferior outcomes although it is stable during the clinical course. The mutation may be used as a biomarker for risk stratification. Am. J. Hematol. 88:E277-E282,

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“…In MDS, SF3B1 mutations cluster with the presence of ring sideroblasts 3 and might be associated with better prognosis, although other investigators have questioned the histopathology-independent prognostic effect of the mutation in MDS. [22][23][24][25] In CLL, SF3B1 mutations were associated with deletions of chromosomal region 11q22 and ATM mutations (ATM is located at chromosome 11q22), as well as poor prognosis and resistance to fludarabine therapy. 4,6,26 OTHER SPLICEOSOME MUTATIONS In MDS, eight genes encoding proteins involved in RNA splicing are mutated with a variable frequency.…”

Section: Sf3b1 Mutationsmentioning

confidence: 99%

“…44 It is intriguing that several steps of the biology of RNA maturation, transport, translation and degradation appear to be targeted in the processes of malignant transformation (Figure 1). 26 7.5% (27/360) Quesada et al 6 9.7% (27/279) Wang et al 4 15% (14/91) SF3B1 in MDS Papaemmanuil et al 3 20.3% (72/354) Patnaik et al 23 49.5% (53/107) RS patients only Damm et al 22 14.7% (47/317) Malcovati et al 25 28 3 4.7% (5/106) Malcovati et al 25 6.5% (4/67) SF3B1 in Myelofibrosis Lasho et al 71 6.5% (19/155) Leukemia 2011 Papaemmanuil et al 3 4.4% (6/136) SF3B1 in AML Malcovati et al 25 5.3% (2/38) sAML only Yoshida et al 1 3.2% (7/213) Papaemmanuil et al 3 5.3% (3/57)…”

Section: Sf3b1 Mutationsmentioning

confidence: 99%

Spliceosome and other novel mutations in chronic lymphocytic leukemia and myeloid malignancies

et al. 2012

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Spliceosome mutations represent a new generation of acquired genetic alterations that affect both myeloid and lymphoid malignancies. A substantial proportion of patients with myelodysplastic syndromes (MDSs) or chronic lymphocytic leukemia (CLL) harbor such mutations, which are often missense in type. Genotype-phenotype associations have been demonstrated for one of these mutations, SF3B1, with ring sideroblasts in MDS and 11q22 deletions in CLL. Spliceosome mutations might result in defective spliceosome assembly, deregulated global mRNA splicing, nuclear-cytoplasm export and altered expression of multiple genes. Such mutations are infrequent in other lymphomas, which instead display a separate group of novel mutations involving genes whose products are believed to affect histone acetylation and methylation and chromatin structure (for example, EZH2 and MLL2). On the other hand, some mutations (for example, NOTCH1) occur in both CLL and other immature and mature lymphoid malignancies. In the current review, we discuss potential mechanisms of cell transformation associated with spliceosome mutations, touch upon the increasing evidence regarding the clonal involvement of hematopoietic stem cells in some cases of otherwise mature lymphoid disorders and summarize recent information on recently described mutations in lymphomas. Leukemia (2012Leukemia ( ) 26, 2027Leukemia ( -2031 doi:10.1038/leu.2012 Keywords: CLL; MDS; mutations; spliceosome INTRODUCTIONIn a series of recently published work, the coding sequences of the DNA obtained from mononuclear cells of the bone marrow of patients with myelodysplastic syndromes (MDSs) were compared with presumably germline DNA (T lymphocytes or buccal swab). [1][2][3] The results have included identification of approximately 10 acquired mutations per patient sample and confirmation of the frequency of previously recognized mutations. 1 More importantly, the particular studies revealed the existence of mutations in genes whose products are involved in controlling the mechanism of splicing of pre-messenger RNA. Such mutations were mutually exclusive and were detected in 45-85% of patients with MDS; 1 the majority constituted missense mutations located in restricted regions of proteins.A similar analysis was conducted in chronic lymphocytic leukemia (CLL) where DNA from tumor cells (CD19 þ and CD5 þ lymphocytes) was compared with that of non-tumor cells (granulocytes or fibroblasts). [4][5][6][7] In addition to genes already known to be mutated in this disease, such as TP53 and ATM, 11 genes were found to be recurrently affected. 4,6 The pathway analyses predicted that these mutations affected DNA damage repair and cell cycle, the Wnt, NOTCH1 and inflammatory/TLR signaling pathways, and, as was the case in MDS, control of splicing mechanisms. 4 The common novel observation, from the above-mentioned studies, in both MDS and CLL, was the identification of mutations in genes whose products are involved in the control of RNA splicing. 8 The involvement of oncogenes in RNA processing h...

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SF3B1 mutations in myelodysplastic syndromes: clinical associations and prognostic implications

Cited by 80 publications

References 15 publications

The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial

The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial

Clinical implications of U2AF1 mutation in patients with myelodysplastic syndrome and its stability during disease progression

Spliceosome and other novel mutations in chronic lymphocytic leukemia and myeloid malignancies

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