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FLT3-ITD regulation of the endoplasmic reticulum functions in acute myeloid leukemia
María Turos-Cabal1,2,3, Ana M Sánchez-Sánchez1,2,3, Noelia Puente-Moncada1,2,3
1Morphology and Cellular Biology Department, University of Oviedo, Oviedo, Spain.
Abstract:
The FLT3-ITD mutation represents the most frequent genetic alteration in newly diagnosed acute myeloid leukemia (AML) patient and is associated with poor prognosis. Mutation result in the retention of a constitutively active form of this receptor in the endoplasmic reticulum (ER) and the subsequent modification of its downstream effectors. Here, we assessed the impact of such retention on ER homeostasis and found that mutant cells present lower levels of ER stress due to the overexpression of ERO1α, one of the main proteins of the protein folding machinery at the ER. Overexpression of ERO1α resulted essential for ITD mutant cells survival and chemoresistance and also played a crucial role in shaping the type of glucose metabolism in AML cells, being the mitochondrial pathway the predominant one in those with a higher ER stress (non-mutated cells) and the glycolytic pathway the predominant one in those with lower ER stress (mutated cells). Our data indicate that FLT3 mutational status dictates the route for glucose metabolism in an ERO1α depending on manner and this provides a survival advantage to tumors carrying these ITD mutations.
Insights
The FLT3-ITD mutation in acute myeloid leukemia (AML) lowers ER stress via ERO1α, shifting glucose metabolism to glycolysis for cell survival and chemoresistance.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Metabolism
Background:
- FLT3-ITD mutations are common in acute myeloid leukemia (AML) and linked to poor outcomes.
- These mutations cause a constitutively active FLT3 receptor to be retained in the endoplasmic reticulum (ER).
Purpose of the Study:
- To investigate how FLT3-ITD mutation-induced ER retention affects ER homeostasis.
- To determine the role of ER stress and ERO1α in the metabolic reprogramming of AML cells with FLT3-ITD mutations.
Main Methods:
- Analysis of ER stress markers in AML cells with and without FLT3-ITD mutations.
- Assessment of ERO1α expression and its functional impact on cell survival and chemoresistance.
- Evaluation of glucose metabolism pathways (mitochondrial vs. glycolytic) in relation to FLT3 mutational status and ER stress levels.
Main Results:
- AML cells with FLT3-ITD mutations exhibit reduced ER stress due to ERO1α overexpression.
- ERO1α overexpression is critical for the survival and chemoresistance of FLT3-ITD mutant AML cells.
- FLT3 mutational status, via ERO1α, dictates glucose metabolism: mutated cells favor glycolysis, while non-mutated cells utilize mitochondrial pathways.
Conclusions:
- FLT3-ITD mutation status influences ER homeostasis and metabolic reprogramming in AML.
- ERO1α plays a key role in mediating the survival advantage conferred by FLT3-ITD mutations through metabolic adaptation.
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