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Acha, Pamela

Adema, Vera

Al Atrash, Gheath

Bejar, Rafael

Blobel, Gerd A

Bueso-Ramos, Carlos

Carew, Jennifer S

Cassari, Margherita

Clise-Dwyer, Karen

Colla, Simona

Ganan-Gomez, Irene

Garcia-Manero, Guillermo, MD

Halene, Stephanie

Kanagal-Shamanna, Rashmi

Lockyer, Pamela

Ma, Feiyang

Maciejewski, Jaroslaw P

Montalban-Bravo, Guillermo

Pellegrini, Matteo

Peslak, Scott A

Santini, Valeria

Sole, Francesc

Song, Yuanbin

Tan, Tuyet M

Thongon, Natthakan

Visconte, Valeria

Wang, Feng

Yang, Hui

English

PubMed

SF3B1 -mutant MDS-RS is associated with buildup of erythroid progenitor cells upregulating EIF2AK1-associated heme deficiency response and autophagy genes. Targeting EIF2AK1 relieves the dysregulated progenitor phenotype. 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

Ademà, Vera

Peslak, Scott A.

Sole, F

Maciejewski, Jaroslaw

Gañán-Gómez, Irene

Tan, Tuyet M.

Carew, Jennifer S.

Al-Atrash, Gheath

Garcia-Manero, Guillermo

Blobel, Gerd A.

Diposit Digital de Documents de la UAB

Targeting the EIF2AK1 Signaling Pathway Rescues Red Blood Cell Production in SF3B1 -Mutant Myelodysplastic Syndromes With Ringed Sideroblasts

OpenWorks @ MD Anderson

Leading Edge of Cancer Research SymposiumNovember 17-18, 2022Targeting the EIF2AK1 Signaling Pathway Rescues Red Blood Cell Production in SF3B1 Mutant Myelodysplastic Syndromes With Ringed SideroblastsVera Adema, Feiyang Ma, Rashmi Kanagal-Shamanna, Natthakan Thongon, Guillermo Montalban-Bravo, Hui Yang, Scott A. Peslak, Feng Wang, Pamela Acha, Francesc Sole, Pamela Lockyer, Margherita Cassari, Jaroslaw P. Maciejewski, Valeria Visconte, Irene Gañán-Gómez, Yuanbin Song, Carlos Bueso-Ramos, Matteo Pellegrini, Tuyet M. Tan, Rafael Bejar, Jennifer S. Carew, Stephanie Halene, Valeria Santini, Gheath Al-Atrash, Karen Clise-Dwyer Guillermo Garcia-Manero, Gerd A. Blobel, and Simona CollaRinged SideroblastsIneffective erythropoiesis SF3B1MTWe profiled the hematopoietic landscape of SF3B1MT MDS-RS at the single-cell levelSF3B1MT MDS-RS at the Single Cell LevelLin-CD34+ HSPCs  Increased Ery/Mk differentiation Metabolic activation in SF3B1-mutant cellsSF3B1MT Lin-CD34+ HSPCs:BM-MNCsEryEry Increased Erythroblast at the Orthochromatic stageSF3B1MT MNCs:EIF2AK1 Depletion Overcomes SF3B1MT- Induced Arrest in Terminal Erythroid Differentiation Terminally differentiated cells Depletion of EIF2AK1 induces differentiation of ringed sideroblasts. EIF2AK1 as a new pharmacological target for patients with MDS-RS with SF3B1 mutationsSummaryV Adema et al., Blood Cancer Discov 2022

Targeting the EIF2AK1 Signaling Pathway  Rescues Red Blood Cell Production in SF3B1 Mutant Myelodysplastic Syndromes With Ringed Sideroblasts

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. This article is highlighted in the In This Issue feature, p. 47

Maciejewski, Jaroslaw P.

PubMed Central

Targeting the EIF2AK1 Signaling Pathway Rescues Red Blood Cell Production in SF3B1-Mutant Myelodysplastic Syndromes With Ringed Sideroblasts

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.SignificanceMDS-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

eScholarship - University of California

Targeting the EIF2AK1 signaling pathway rescues red blood cell production in SF3B1-mutant myelodysplastic syndromes with ringed sideroblasts

http://dx.doi.org/10.1158/2643-3230.BCD-21-0220

Targeting the EIF2AK1 Signaling Pathway Rescues Red Blood Cell Production in SF3B1 Mutant Myelodysplastic Syndromes With Ringed Sideroblasts

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PubMed Central

eScholarship - University of California