Splicing factor mutations in MDS RARS and MDS/MPN-RS-T

Yoshimi, Akihide; Abdel‐Wahab, Omar

doi:10.1007/s12185-017-2242-0

Cited by 17 publications

(12 citation statements)

References 80 publications

(93 reference statements)

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“…We also identified differential enrichment of signaling pathways depending on SF3B1 mutation and tumor types, including activation of NOTCH signaling in SF3B1-mutant CLL (13) and heme metabolism and NF-κB signaling (core enriched genes: proteasome genes) in patients with SF3B1-mutant MDS (Supplementary Table S4; refs. 14,15). In addition, activation of multiple oncogenic pathways such as the ERK/MAPK, mTOR, and apoptosis-related pathways was suggested in SF3B1-mutant tumorigenesis (Supplementary Table S4).…”

Section: Pan-cancer Analysis Identified Differential Splicing Events Based On Lineage and Sf3b1 Mutant Allelementioning

confidence: 99%

Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization

et al. 2020

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Although mutations in the gene encoding the RNA splicing factor SF3B1 are frequent in multiple cancers, their functional effects and therapeutic dependencies are poorly understood. Here, we characterize 98 tumors and 12 isogenic cell lines harboring SF3B1 hotspot mutations, identifying hundreds of cryptic 3′ splice sites common and specific to different cancer types. Regulatory network analysis revealed that the most common SF3B1 mutation activates MYC via effects conserved across human and mouse cells. SF3B1 mutations promote decay of transcripts encoding the protein phosphatase 2A (PP2A) subunit PPP2R5A, increasing MYC S62 and BCL2 S70 phosphorylation which, in turn, promotes MYC protein stability and impair apoptosis, respectively. Genetic PPP2R5A restoration or pharmacologic PP2A activation impaired SF3B1-mutant tumorigenesis, elucidating a therapeutic approach to aberrant splicing by mutant SF3B1.SigNiFiCANCe: Here, we identify that mutations in SF3B1, the most commonly mutated splicing factor gene across cancers, alter splicing of a specific subunit of the PP2A serine/threonine phosphatase complex to confer post-translational MYC and BCL2 activation, which is therapeutically intervenable using an FDA-approved drug.

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Section: Pan-cancer Analysis Identified Differential Splicing Events Based On Lineage and Sf3b1 Mutant Allelementioning

confidence: 99%

Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization

et al. 2020

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“…Factors involved with pre-mRNA processing are commonly mutated in human hematopoietic diseases, especially those resulting in anemia and erythropoietic dysplasia. [2][3][4] For example, Splicing Factor 3B, subunit 1 (SF3B1), a core component of the spliceosome, is one of the most prevalently mutated factors in myelodysplastic syndromes (MDS). [2][3][4] Mutations in SF3B1 correlate strongly with a subcategory of MDSs characterized by refractory anemia with ring sideroblasts, [5][6][7] although the exact mechanism that connects genotype to phenotype has not been found.…”

Section: Introductionmentioning

confidence: 99%

“…[2][3][4] For example, Splicing Factor 3B, subunit 1 (SF3B1), a core component of the spliceosome, is one of the most prevalently mutated factors in myelodysplastic syndromes (MDS). [2][3][4] Mutations in SF3B1 correlate strongly with a subcategory of MDSs characterized by refractory anemia with ring sideroblasts, [5][6][7] although the exact mechanism that connects genotype to phenotype has not been found. Additionally, SF3B1 itself undergoes extensive alternative splicing during erythroid differentiation, suggesting that SF3B1 could have discrete roles in distinct stages of erythropoiesis.…”

Section: Introductionmentioning

confidence: 99%

The splicing factor Sf3b1 regulates erythroid maturation and proliferation via TGFβ signaling in zebrafish

Garza

Cameron

Gupta³

et al. 2019

Blood Advances

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The spliceosomal component Splicing Factor 3B, subunit 1 (SF3B1) is one of the most prevalently mutated factors in the bone marrow failure disorder myelodysplastic syndrome. There is a strong clinical correlation between SF3B1 mutations and erythroid defects, such as refractory anemia with ringed sideroblasts, but the role of SF3B1 in normal erythroid development is largely unknown. Loss-of-function zebrafish mutants for sf3b1 develop a macrocytic anemia. Here, we explore the underlying mechanism for anemia associated with sf3b1 deficiency in vivo. We found that sf3b1 mutant erythroid progenitors display a G0/G1 cell-cycle arrest with mutant erythrocytes showing signs of immaturity. RNA-sequencing analysis of sf3b1 mutant erythroid progenitors revealed normal expression of red blood cell regulators such as gata1, globin genes, and heme biosynthetic factors, but upregulation of genes in the transforming growth factor β (TGFβ) pathway. As TGFβ signaling is a known inducer of quiescence, the data suggest that activation of the pathway could trigger sf3b1 deficiency–induced anemia via cell-cycle arrest. Indeed, we found that inhibition of TGFβ signaling released the G0/G1 block in erythroid progenitors. Surprisingly, removal of this checkpoint enhanced rather than suppressed the anemia, indicating that the TGFβ-mediated cell-cycle arrest is protective for sf3b1-mutant erythrocytes. Together, these data suggest that macrocytic anemia arising from Sf3b1 deficiency is likely due to pleiotropic and distinct effects on cell-cycle progression and maturation.

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“…There is growing evidence that abnormalities in certain genes can result either in myeloid or in lymphoid malignancies. This is particularly true for the BCR/ABL1 fusion gene and the PDGFRA , PDGFRB , and FGFR1 genes [22] as well as for TET2 mutations, observed in MDS, CMML, and in B and mainly T LPDs [23], for SF3B1 mutations, associated with both the MDS-RS phenotype and B-CLL [24, 25].…”

Section: Discussionmentioning

confidence: 99%

Coexistence of Myeloid and Lymphoid Neoplasms: A Single-Center Experience

Bouchla

Thomopoulos

Tsirigotis

et al. 2019

Advances in Hematology

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The coexistence of a myeloid and a lymphoid neoplasm in the same patient is a rare finding. We retrospectively searched the records of the Hematology Division of the Second Department of Internal Medicine and Research Institute at Attikon University General Hospital of Athens from 2003 to 2018. Nine cases have been identified in a total of 244 BCR-/ABL1- negative MPN and 25 MDS/MPN patients and 1062 LPD patients referred to our institution between 2003 and 2018. Each case is distinct in the diversity of myeloid and lymphoid entities, the chronological occurrence of the two neoplasms, and the patient clinical course. All of them exhibit myeloproliferative (6 JAK2 V617F-positive cases) and lymphoproliferative features, with 1 monoclonal B-cell lymphocytosis (MBL), 3 B-chronic lymphocytic leukemias (B-CLL), 3 B-non-Hodgkin lymphomas (B-NHL), 1 multiple myeloma (MM), and 1 light and heavy deposition disease (LHCDD), while in three cases myelodysplasia is also present. The challenges in identifying and dealing with these rare situations in everyday clinical practice are depicted in this article.

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Splicing factor mutations in MDS RARS and MDS/MPN-RS-T

Cited by 17 publications

References 80 publications

Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization

Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization

The splicing factor Sf3b1 regulates erythroid maturation and proliferation via TGFβ signaling in zebrafish

Coexistence of Myeloid and Lymphoid Neoplasms: A Single-Center Experience

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