SF3B1 mutations are infrequently found in non-myelodysplastic bone marrow failure syndromes and mast cell diseases but, if present, are associated with the ring sideroblast phenotype

Visconte, Valeria; Tabarroki, Ali; Rogers, Heesun J.; Hasrouni, Edy; Traina, Fabı́ola; Makishima, Hideki; Hamilton, Betty K.; Liu, Yang; O’Keefe, Christine L.; Lichtin, Alan E.; Horwitz, Leonard; Sekeres, Mikkael A.; Hsieh, Fred H.; Tiu, Ramon V.

doi:10.3324/haematol.2013.090506

Cited by 12 publications

(7 citation statements)

References 15 publications

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“…12,26,[28][29][30] Other studies suggested the relationship between SF3B1 mutations and mitochondrial proteins but did not delve into the specific mechanisms or pathways that contribute to iron accumulation or disease phenotype in SF3B1-mutant MDS. 10,31 Using TEM, we found that within RARS/-T, sideroblasts of SF3B1-mutant patients have distinct ultrastructural iron distribution characterized by abundant iron deposits compared with those of WT patients.…”

Section: Discussionmentioning

confidence: 99%

Distinct iron architecture in SF3B1-mutant myelodysplastic syndrome patients is linked to an SLC25A37 splice variant with a retained intron

et al. 2014

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Perturbation in iron homeostasis is a hallmark of some hematologic diseases. Abnormal sideroblasts with accumulation of iron in the mitochondria are named ring sideroblasts (RS). RS is a cardinal feature of refractory anemia with RS (RARS) and RARS with marked thrombocytosis (RARS/-T). Mutations in SF3B1, a member of the RNA splicing machinery are frequent in RARS/-T and defects of this gene were linked to RS formation. Here we showcase the differences in iron architecture of SF3B1-mutant and wild-type (WT) RARS/-T and provide new mechanistic insights by which SF3B1 mutations lead to differences in iron. We found higher iron levels in SF3B1 mutant vs WT RARS/-T by transmission electron microscopy/spectroscopy/flow cytometry. SF3B1 mutations led to increased iron without changing the valence as shown by the presence of Fe(2+) in mutant and WT. Reactive oxygen species and DNA damage were not increased in SF3B1-mutant patients. RNA-sequencing and Reverse transcriptase PCR showed higher expression of a specific isoform of SLC25A37 in SF3B1-mutant patients, a crucial importer of Fe(2+) into the mitochondria. Our studies suggest that SF3B1 mutations contribute to cellular iron overload in RARS/-T by deregulating SLC25A37.

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Section: Discussionmentioning

confidence: 99%

Distinct iron architecture in SF3B1-mutant myelodysplastic syndrome patients is linked to an SLC25A37 splice variant with a retained intron

et al. 2014

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“…4 Splicing, the removal of introns and joining of exons from nascent pre-mRNA, has gained attention as a target for cancer therapy given the distinct splicing patterns identified both in tumor cells and metastatic tumor populations. 5,6 Recently, a series of studies identified heterozygous missense mutations in U2AF1 and splicing factor 3B subunit 1 (SF3B1) genes associated with myelodysplastic syndromes, and have shown that SF3B1 is frequently mutated in myelodysplastic syndromes, 7,8 and CLL. 9,10 This, combined with the identification of small molecules that target the spliceosome, motivated us to explore the application of these agents to CLL.…”

Section: Introductionmentioning

confidence: 99%

Targeting the spliceosome in chronic lymphocytic leukemia with the macrolides FD-895 and pladienolide-B

et al. 2015

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“…On the other hand, p.Lys700Glu is the most frequent SF3B1 mutation among hematological diseases which is associated with an abnormal selection of the 3' splice sites for a group of transcripts, including the iron transporter ABCB7, leading to a refractory anemia with ringed sideroblasts [22][23][24]. This mutation is very infrequent in SM and is associated with the ring sideroblast phenotype [7].…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the splicing factor 3B1 gene (SF3B1) are frequent in myelodysplastic syndromes (MDS) with ring sideroblasts. These mutations have been associated with good outcomes [7]. SF3B1 mutations are sometimes found in patients with ring sideroblasts (< 10%) and chronic myelomonocytic leukemia.…”

Section: Case Reportmentioning

confidence: 99%

Molecular Landscape and Clonal Evolution of Acute Mast Cell Leukemia: Case Study

Ricardo¹,

Liz²,

M³

et al. 2018

J Genet Genome Res

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Systemic mastocytosis is a rare disorder characterized by clonal proliferation, which results in abnormally high numbers of mast cells in the skin, bone marrow, and internal organs, such as liver, spleen, or lymph nodes. Mast cell leukemia and subvariants were stratified by the World Health Organization in 2016, as a subtype of systemic mastocytosis. Here, we present a case of acute mast cell leukemia that was imatinib-sensitive, with well-known mutations in the oncogene, KIT (c.1565 T > G p.Phe522Cys), and in the splicing factor gene, SF3B1 (c.2098 A > G, p.Lys700Glu). Molecular cytogenetic studies showed that 26% of cells harbored the 46,XX,der(5)t(5;6)(q35;q24),t(10;16)(q26;q23) karyotype abnormality, confirmed with the fluorescence in-situ hybridization technique. Additionally, the patient showed severe hepatosplenomegaly with multiple retroperitoneal, mesenteric, and axillary adenopathies. Although the prognostic survival of patients with mast cell leukemia is around 6 months, this rare case, with a low-frequency (< 5%) p.Phe-522Cys KIT mutation, was associated with complete remission and negative minimal residual disease, which lasted for 2.5 years; moreover, the mutation was not detectable after imatinib treatment. When the patient relapsed, the two mutations studied in KIT and SF3B1 genes reappeared, and a new clone emerged with the variant c.2465 A > C p.Asn-822Thr, located in the activation loop of the KIT protein. Molecular analyses of the KIT gene were essential for selecting the appropriate tyrosine-kinase inhibitor. Accurate drug selection can prevent possible resistance and facilitate adequate treatment of subsequent relapses.

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SF3B1 mutations are infrequently found in non-myelodysplastic bone marrow failure syndromes and mast cell diseases but, if present, are associated with the ring sideroblast phenotype

Cited by 12 publications

References 15 publications

Distinct iron architecture in SF3B1-mutant myelodysplastic syndrome patients is linked to an SLC25A37 splice variant with a retained intron

Distinct iron architecture in SF3B1-mutant myelodysplastic syndrome patients is linked to an SLC25A37 splice variant with a retained intron

Targeting the spliceosome in chronic lymphocytic leukemia with the macrolides FD-895 and pladienolide-B

Molecular Landscape and Clonal Evolution of Acute Mast Cell Leukemia: Case Study

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