FLT3-ITD regulation of the endoplasmic reticulum functions in acute myeloid leukemia

IF 3.3 4区 医学 Q2 HEMATOLOGY
María Turos-Cabal, Ana M. Sánchez-Sánchez, Noelia Puente-Moncada, Federico Herrera, Isaac Antolin, Carmen Rodríguez, Vanesa Martín
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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.

Abstract Image

FLT3-ITD 对急性髓性白血病内质网功能的调控。
FLT3-ITD突变是新诊断的急性髓性白血病(AML)患者中最常见的基因改变,与预后不良有关。突变导致这种受体的组成活性形式保留在内质网(ER)中,并随后改变其下游效应物。在这里,我们评估了这种保留对ER平衡的影响,发现突变细胞由于ER上蛋白质折叠机制的主要蛋白之一ERO1α的过度表达而出现较低水平的ER应激。ERO1α的过度表达对ITD突变细胞的存活和化疗抗性至关重要,而且在形成急性髓细胞葡萄糖代谢类型方面也起着关键作用,在ER应激较高的细胞(非突变细胞)中,线粒体途径占主导地位,而在ER应激较低的细胞(突变细胞)中,糖酵解途径占主导地位。我们的数据表明,FLT3突变状态决定了葡萄糖代谢的途径,其方式取决于ERO1α,这为携带这些ITD突变的肿瘤提供了生存优势。
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来源期刊
Hematological Oncology
Hematological Oncology 医学-血液学
CiteScore
4.20
自引率
6.10%
发文量
147
审稿时长
>12 weeks
期刊介绍: Hematological Oncology considers for publication articles dealing with experimental and clinical aspects of neoplastic diseases of the hemopoietic and lymphoid systems and relevant related matters. Translational studies applying basic science to clinical issues are particularly welcomed. Manuscripts dealing with the following areas are encouraged: -Clinical practice and management of hematological neoplasia, including: acute and chronic leukemias, malignant lymphomas, myeloproliferative disorders -Diagnostic investigations, including imaging and laboratory assays -Epidemiology, pathology and pathobiology of hematological neoplasia of hematological diseases -Therapeutic issues including Phase 1, 2 or 3 trials as well as allogeneic and autologous stem cell transplantation studies -Aspects of the cell biology, molecular biology, molecular genetics and cytogenetics of normal or diseased hematopoeisis and lymphopoiesis, including stem cells and cytokines and other regulatory systems. Concise, topical review material is welcomed, especially if it makes new concepts and ideas accessible to a wider community. Proposals for review material may be discussed with the Editor-in-Chief. Collections of case material and case reports will be considered only if they have broader scientific or clinical relevance.
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