Loss of erythroblasts in acute myeloid leukemia causes iron redistribution with clinical implications

Abstract Acute myeloid leukemia (AML) is a heterogeneous disease with poor prognosis and limited treatment strategies. Determining the role of cell-extrinsic regulators of leukemic cells is vital to gain clinical insights into the biology of AML. Iron is a key extrinsic regulator of cancer but its s...

Full description

Saved in:
Bibliographic Details
Published inbioRxiv
Main Authors Lopes, Marta, Duarte, Tiago L, Teles, Maria J, Mosteo, Laura, Chacim, Sérgio, Aguiar, Eliana, Pereira-Reis, Joana, Oliveira, Mónica, Silva, André M N, Gonçalves, Nuno, Martins, Gabriela, Kong, Isabella Y, Zethoven, Magnus, Vervoort, Stephin, Martins, Sandra, Quintela, Miguel, Hawkins, Edwin D, Trigo, Fernanda, Guimarães, João T, Mariz, José M, Porto, Graça, Duarte, Delfim
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 26.10.2020
Subjects
Acute myeloid leukemia
Diagnosis
Erythroblasts
Ferritin
Hepcidin
Inflammation
Iron
Leukemia
Medical prognosis
Myeloid leukemia
Transferrin
Online AccessGet full text

Cover

More Information
Summary:Abstract Acute myeloid leukemia (AML) is a heterogeneous disease with poor prognosis and limited treatment strategies. Determining the role of cell-extrinsic regulators of leukemic cells is vital to gain clinical insights into the biology of AML. Iron is a key extrinsic regulator of cancer but its systemic regulation remains poorly explored in AML. To address this question, we studied iron metabolism in AML patients at diagnosis and mechanisms involved using the syngeneic MLL-AF9-induced AML mouse model. We found that AML is a disorder with a unique iron profile not associated with inflammation or transfusion and characterized by high ferritin, low transferrin, high transferrin saturation (TSAT), and high hepcidin. The increased TSAT in particular, contrasts with observations in other cancer types and in anemia of inflammation. Using the MLL-AF9 mouse model of AML, we demonstrated that leukemic blasts take up iron and that the AML-induced loss of erythroblasts is responsible for iron redistribution and an increase in TSAT. We also show that elevated TSAT at diagnosis is independently associated with increased overall survival in AML and suggest that TSAT may be a relevant prognostic marker in AML. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2020.10.26.350116