TY - JOUR
T1 - Targeting the EIF2AK1 Signaling Pathway Rescues Red Blood Cell Production in SF3B1-Mutant Myelodysplastic Syndromes With Ringed Sideroblasts
AU - Adema, Vera
AU - Ma, Feiyang
AU - Kanagal-Shamanna, Rashmi
AU - Thongon, Natthakan
AU - Montalban-Bravo, Guillermo
AU - Yang, Hui
AU - Peslak, Scott A.
AU - Wang, Feng
AU - Acha, Pamela
AU - Sole, Francesc
AU - Lockyer, Pamela
AU - Cassari, Margherita
AU - Maciejewski, Jaroslaw P.
AU - Visconte, Valeria
AU - Gañán-Gómez, Irene
AU - Song, Yuanbin
AU - Bueso-Ramos, Carlos
AU - Pellegrini, Matteo
AU - Tan, Tuyet M.
AU - Bejar, Rafael
AU - Carew, Jennifer S.
AU - Halene, Stephanie
AU - Santini, Valeria
AU - Al-Atrash, Gheath
AU - Clise-Dwyer, Karen
AU - Garcia-Manero, Guillermo
AU - Blobel, Gerd A.
AU - Colla, Simona
N1 - Funding Information: J.P. Maciejewski reports grants from the Leukemia and Lymphoma Society, the U.S. Department of Defense, and NIH during the conduct of the study. R. Bejar reports other support from Aptose Biosciences, personal fees from Gilead and Epizyme outside the submitted work. J.S. Carew reports other support from Majestic Therapeutics, LLC outside the submitted work; in addition, J.S. Carew has a patent 9926326 issued. S. Halene reports grants and other support from NIH and other support from The Frederick A DeLuca Foundation during the conduct of the study; personal fees from FORMA Therapeutics outside the submitted work; in addition, S. Halene has a pending patent. V. Santini reports personal fees from BMS, AbbVie, Geron, Gilead, Takeda, Novartis, and Menarini outside the submitted work. K. Clise-Dwyer reports grants from NCI during the conduct of the study. No disclosures were reported by the other authors. Funding Information: This work was supported by philanthropic contributions to The University of Texas MD Anderson AML/MDS Moon Shot, by the NIH through MD Anderson’s Leukemia SPORE grant (P50 CA100632), by a Ladies Leukemia League grant to R. Kanagal-Shamanna, and by an NIH/NIDDK 5U54DK106857 grant to the Animal Modeling Core of the Yale Cooperative Center of Excellence in Hematology. S. Colla is a Scholar of the Leukemia and Lymphoma Society. N. Thongon was supported by the 2020 ASH restart award. This work used MD Anderson’s South Campus Flow Cytometry and Cellular Imaging Core, the Advanced Technology Genomics Core, and the High-Resolution Electron Microscopy Facility, which are supported in part by the NIH (NCI) through MD Anderson’s Cancer Center Support Grant (P30 CA16672). The authors thank Joseph Munch and Kelly Soltysiak for assistance with manuscript editing. Publisher Copyright: © 2022 The Authors; Published by the American Association for Cancer Research.
PY - 2022/11/1
Y1 - 2022/11/1
N2 - 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. SIGNIFICANCE: 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.
AB - 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. SIGNIFICANCE: 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.
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U2 - 10.1158/2643-3230.BCD-21-0220
DO - 10.1158/2643-3230.BCD-21-0220
M3 - Article
SN - 2643-3230
VL - 3
SP - 554
EP - 567
JO - Blood cancer discovery
JF - Blood cancer discovery
IS - 6
ER -