Abstract:
: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.
journal_name
Leukemiajournal_title
Leukemiaauthors
Visconte V,Avishai N,Mahfouz R,Tabarroki A,Cowen J,Sharghi-Moshtaghin R,Hitomi M,Rogers HJ,Hasrouni E,Phillips J,Sekeres MA,Heuer AH,Saunthararajah Y,Barnard J,Tiu RVdoi
10.1038/leu.2014.170subject
Has Abstractpub_date
2015-01-01 00:00:00pages
188-95issue
1eissn
0887-6924issn
1476-5551pii
leu2014170journal_volume
29pub_type
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