Coordinated missplicing of TMEM14C and ABCB7 causes ring sideroblast formation in SF3B1-mutant myelodysplastic syndrome Journal Article
| Authors: | Clough, C. A.; Pangallo, J.; Sarchi, M.; Ilagan, J. O.; North, K.; Bergantinos, R.; Stolla, M. C.; Naru, J.; Nugent, P.; Kim, E.; Stirewalt, D. L.; Subramaniam, A. R.; Abdel-Wahab, O.; Abkowitz, J. L.; Bradley, R. K.; Doulatov, S. |
| Article Title: | Coordinated missplicing of TMEM14C and ABCB7 causes ring sideroblast formation in SF3B1-mutant myelodysplastic syndrome |
| Abstract: | SF3B1 splicing factor mutations are near-universally found in myelodysplastic syndromes (MDS) with ring sideroblasts (RS), a clonal hematopoietic disorder characterized by abnormal erythroid cells with iron-loaded mitochondria. Despite this remarkably strong genotype-to-phenotype correlation, the mechanism by which mutant SF3B1 dysregulates iron metabolism to cause RS remains unclear due to an absence of physiological models of RS formation. Here, we report an induced pluripotent stem cell model of SF3B1-mutant MDS that for the first time recapitulates robust RS formation during in vitro erythroid differentiation. Mutant SF3B1 induces missplicing of ∼100 genes throughout erythroid differentiation, including proposed RS driver genes TMEM14C, PPOX, and ABCB7. All 3 missplicing events reduce protein expression, notably occurring via 5′ UTR alteration, and reduced translation efficiency for TMEM14C. Functional rescue of TMEM14C and ABCB7, but not the non–rate-limiting enzyme PPOX, markedly decreased RS, and their combined rescue nearly abolished RS formation. Our study demonstrates that coordinated missplicing of mitochondrial transporters TMEM14C and ABCB7 by mutant SF3B1 sequesters iron in mitochondria, causing RS formation. © 2022 American Society of Hematology |
| Keywords: | controlled study; protein expression; unclassified drug; gene mutation; human cell; genetics; mutation; phenotype; metabolism; atp-binding cassette transporters; transcription factor; cell differentiation; in vitro study; proteomics; myelodysplastic syndrome; cell culture; messenger rna; breast cancer resistance protein; abc transporter; lentivirus vector; erythroid cell; phosphoproteins; bone marrow cell; mitochondrial protein; transcriptome; mitochondrion; phosphoprotein; myelodysplastic syndromes; mitochondrial dna; rna degradation; mitochondrial proteins; peptides and proteins; refractory anemia with ringed sideroblasts; reticulocyte; induced pluripotent stem cell; iron metabolism; humans; human; article; rna sequencing; mitochondrial dna replication; rna splicing factor; rna splicing factors; bone marrow derived mononuclear cell; heme synthesis; protein splicing; abcb7 protein; ppox protein; tmem14c protein; abcb7 protein, human; flavoprotein; ppox protein, human; protoporphyrinogen oxidase; sf3b1 protein, human; flavoproteins |
| Journal Title: | Blood |
| Volume: | 139 |
| Issue: | 13 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2022-03-31 |
| Start Page: | 2038 |
| End Page: | 2049 |
| Language: | English |
| DOI: | 10.1182/blood.2021012652 |
| PUBMED: | 34861039 |
| PROVIDER: | scopus |
| PMCID: | PMC8972092 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 May 2022 -- Source: Scopus |
