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Altered NFE2 activity predisposes to leukemic transformation and myelosarcoma with AML-specific aberrations.

ABSTRACT: In acute myeloid leukemia (AML), acquired genetic aberrations carry prognostic implications and guide therapeutic decisions. Clinical algorithms have been improved by the incorporation of novel aberrations. Here, we report the presence and functional characterization of mutations in the transcription factor NFE2 in patients with AML and in a patient with myelosarcoma. We previously described NFE2 mutations in patients with myeloproliferative neoplasms and demonstrated that expression of mutant NFE2 in mice causes a myeloproliferative phenotype. Now, we show that, during follow-up, 34% of these mice transform to leukemia presenting with or without concomitant myelosarcomas, or develop isolated myelosarcomas. These myelosarcomas and leukemias acquired AML-specific alterations, including the murine equivalent of trisomy 8, loss of the AML commonly deleted region on chromosome 5q, and mutations in the tumor suppressor Trp53 Our data show that mutations in NFE2 predispose to the acquisition of secondary changes promoting the development of myelosarcoma and/or AML.

SUBMITTER: Jutzi JS

PROVIDER: S-EPMC6484461 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Altered NFE2 activity predisposes to leukemic transformation and myelosarcoma with AML-specific aberrations.

Jutzi Jonas Samuel JS Basu Titiksha T Pellmann Maximilian M Kaiser Sandra S Steinemann Doris D Sanders Mathijs A MA Hinai Adil S A ASA Zeilemaker Annelieke A Bojtine Kovacs Sarolta S Koellerer Christoph C Ostendorp Jenny J Aumann Konrad K Wang Wei W Raffoux Emmanuel E Cassinat Bruno B Bullinger Lars L Schlegelberger Brigitte B Valk Peter J M PJM Pahl Heike Luise HL

Blood 20190212 16

In acute myeloid leukemia (AML), acquired genetic aberrations carry prognostic implications and guide therapeutic decisions. Clinical algorithms have been improved by the incorporation of novel aberrations. Here, we report the presence and functional characterization of mutations in the transcription factor NFE2 in patients with AML and in a patient with myelosarcoma. We previously described NFE2 mutations in patients with myeloproliferative neoplasms and demonstrated that expression of mutant N ...[more]

PMID: 30755419

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Project description:During embryo development, the heart is the first functioning organ. Although quiescent in the adult, the epicardium is essential during development to form a normal four-chambered heart. Epicardial-derived cells contribute to the heart as it develops with fibroblasts and vascular smooth muscle cells. Previous studies have shown that a heartbeat is required for epicardium formation, but no study to our knowledge has shown the effects of haemodynamic changes on the epicardium. Since the aetiologies of many congenital heart defects are unknown, we suggest that an alteration in the heart's haemodynamics might provide an explanatory basis for some of them. To change the heart's haemodynamics, outflow tract (OFT) banding using a double overhang knot was performed on HH21 chick embryos, with harvesting at different developmental stages. The epicardium of the heart was phenotypically and functionally characterised using a range of techniques. Upon alteration of haemodynamics, the epicardium exhibited abnormal morphology at HH29, even though migration of epicardial cells along the surface of the heart was found to be normal between HH24 and HH28. The abnormal epicardial phenotype was exacerbated at HH35 with severe changes in the structure of the extracellular matrix (ECM). A number of genes tied to ECM production were also differentially expressed in HH29 OFT-banded hearts, including DDR2 and collagen XII. At HH35, the differential expression of these genes was even greater with additional downregulation of collagen I and TCF21. In this study, the epicardium was found to be severely impacted by altered haemodynamics upon OFT banding. The increased volume of the epicardium at HH29, upon OFT-banding, and the expression changes of ECM markers were the first indicative signs of aberrations in epicardial architecture; by HH35, the phenotype had progressed. The decrease in epicardial thickness at HH35 suggests an increase in tension, with a force acting perpendicular to the surface of the epicardium. Although the developing epicardium and the blood flowing through the heart are separated by the endocardium and myocardium, the data presented here demonstrate that altering the blood flow affects the structure and molecular expression of the epicardial layer. Due to the intrinsic role the epicardium in cardiogenesis, defects in epicardial formation could have a role in the formation of a wide range of congenital heart defects.

Dataset Information

Altered NFE2 activity predisposes to leukemic transformation and myelosarcoma with AML-specific aberrations.

Publications

Altered NFE2 activity predisposes to leukemic transformation and myelosarcoma with AML-specific aberrations.

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