Loss of erythroblasts in acute myeloid leukemia causes iron redistribution with clinical implications
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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 patients with AML at diagnosis and explored the 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, 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 the AML-induced loss of erythroblasts is responsible for iron redistribution and increased TSAT. We also show that AML progression is delayed in mouse models of systemic iron overload and that elevated TSAT at diagnosis is independently associated with increased overall survival in AML. We suggest that TSAT may be a relevant prognostic marker in AML.
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This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/21282948.
Major issues
1. Reliance on a single AML mouse model
The study relies almost exclusively on the MLL-AF9 syngeneic AML model. Given the marked biological heterogeneity of AML, validation in additional murine models (e.g., C1498) and human xenograft models (e.g., OCI-AML3 in NSG-SGM3 mice) would considerably strengthen the generalizability and translational relevance of the findings.
2. Lack of pharmacological rescue experiments
Although the authors demonstrate that iron redistribution accompanies AML progression, they do not perform rescue experiments to establish causality. Pharmacological modulation of iron using agents such as Deferoxamine (DFO) or Ferumoxytol (Feraheme) would help …
This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/21282948.
Major issues
1. Reliance on a single AML mouse model
The study relies almost exclusively on the MLL-AF9 syngeneic AML model. Given the marked biological heterogeneity of AML, validation in additional murine models (e.g., C1498) and human xenograft models (e.g., OCI-AML3 in NSG-SGM3 mice) would considerably strengthen the generalizability and translational relevance of the findings.
2. Lack of pharmacological rescue experiments
Although the authors demonstrate that iron redistribution accompanies AML progression, they do not perform rescue experiments to establish causality. Pharmacological modulation of iron using agents such as Deferoxamine (DFO) or Ferumoxytol (Feraheme) would help determine whether altering iron availability directly influences leukemia progression and iron redistribution.
3. Limited experimental group design
Most experiments compare only Control and AML mice. A more informative design would include additional therapeutic groups such as:
Control
AML
AML + Chemotherapy
AML + Chemotherapy + DFO
or
Control
AML
AML + DFO
AML + Chemotherapy
AML + Chemotherapy + DFO
These groups would clarify whether chemotherapy-induced changes in iron metabolism are mechanistically responsible for hematopoietic recovery and improved survival rather than being secondary consequences of tumor cell death.
4. Limited mechanistic evaluation of leukemia burden
Although survival and iron parameters were extensively analyzed, additional quantitative assessment of leukemia burden (AML cell frequency and absolute cell number in peripheral blood, bone marrow, and spleen) across treatment groups would strengthen the mechanistic interpretation of the observed survival benefit.
Minor issues
1. Bone marrow vascular niche was not evaluated
The study does not investigate whether iron redistribution affects the bone marrow vascular microenvironment. Assessing bone marrow vasculature (e.g., Endomucin-positive area and endothelial cell abundance) would provide additional insight into microenvironmental remodeling during AML progression.
2. Endothelial iron accumulation was not examined
Intracellular iron accumulation was assessed only in AML cells. Measuring intracellular Fe²⁺ in bone marrow endothelial cells would help determine whether iron redistribution also affects the vascular niche.
3. Oxidative stress markers were not assessed
Because excessive iron can promote oxidative damage, evaluation of lipid ROS or ferroptosis-related markers would strengthen the proposed mechanistic link between iron accumulation and tissue dysfunction.
4. Bone marrow cellularity was not quantified
Direct measurement of total bone marrow cellularity would complement the erythroblast analysis and provide a broader assessment of hematopoietic alterations during AML progression.
5. Limited assessment of cell proliferation
The study does not comprehensively evaluate proliferative activity (e.g., Ki67-positive cells) across different bone marrow cell populations. Such analysis could help distinguish whether iron redistribution is associated with altered cellular proliferation.
6. Adaptive immune compartment was not explored
The potential contribution of adaptive immune cells, including CXCR5⁺ lymphocytes (e.g., T follicular helper cells), was not investigated. Furthermore, the use of Rag2⁻/⁻ mice could have helped determine whether adaptive immunity contributes to the observed phenotype, although this falls outside the primary objective of the study.
Competing interests
The author declares that they have no competing interests.
Use of Artificial Intelligence (AI)
The author declares that they used generative AI to come up with new ideas for their review.
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