Targeting the EIF2AK1 Signaling Pathway Rescues Red Blood Cell Production in SF3B1-Mutant Myelodysplastic Syndromes With Ringed Sideroblasts.
Journal
Blood cancer discovery
ISSN: 2643-3249
Titre abrégé: Blood Cancer Discov
Pays: United States
ID NLM: 101764786
Informations de publication
Date de publication:
02 11 2022
02 11 2022
Historique:
received:
29
11
2021
revised:
26
04
2022
accepted:
29
07
2022
pubmed:
5
8
2022
medline:
4
11
2022
entrez:
4
8
2022
Statut:
ppublish
Résumé
SF3B1 mutations, which occur in 20% of patients with myelodysplastic syndromes (MDS), are the hallmarks of a specific MDS subtype, MDS with ringed sideroblasts (MDS-RS), which is characterized by the accumulation of erythroid precursors in the bone marrow and primarily affects the elderly population. Here, using single-cell technologies and functional validation studies of primary SF3B1-mutant MDS-RS samples, we show that SF3B1 mutations lead to the activation of the EIF2AK1 pathway in response to heme deficiency and that targeting this pathway rescues aberrant erythroid differentiation and enables the red blood cell maturation of MDS-RS erythroblasts. These data support the development of EIF2AK1 inhibitors to overcome transfusion dependency in patients with SF3B1-mutant MDS-RS with impaired red blood cell production. MDS-RS are characterized by significant anemia. Patients with MDS-RS die from a shortage of red blood cells and the side effects of iron overload due to their constant need for transfusions. Our study has implications for the development of therapies to achieve long-lasting hematologic responses. This article is highlighted in the In This Issue feature, p. 476.
Identifiants
pubmed: 35926182
pii: 709896
doi: 10.1158/2643-3230.BCD-21-0220
pmc: PMC9894566
doi:
Substances chimiques
RNA Splicing Factors
0
Phosphoproteins
0
SF3B1 protein, human
0
EIF2AK1 protein, human
EC 2.7.11.1
eIF-2 Kinase
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
554-567Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA100632
Pays : United States
Organisme : NIDDK NIH HHS
ID : U54 DK106857
Pays : United States
Organisme : NIDDK NIH HHS
ID : K08 DK129716
Pays : United States
Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
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