ENOX2 NADH Oxidase: A BCR-ABL1-dependent cell surface and secreted redox protein in chronic myeloid leukemia (CML)

Baykal Kose, S.; Voldoire, M.; Desterke, C.; Sorel, N.; Cayssials, E.; Johnson-Ansah, H.; Guerci-Bresler, A.; Bennaceur-Griscelli, A.; Chomel, J. C.; Turhan, A. G.

doi:10.1101/2021.01.23.427819

bioRxiv · 10.1101/2021.01.23.427819

ENOX2 NADH Oxidase: A BCR-ABL1-dependent cell surface and secreted redox protein in chronic myeloid leukemia (CML)

Baykal Kose, S.·Voldoire, M.·Desterke, C.·Sorel, N.·Cayssials, E.·Johnson-Ansah, H.·Guerci-Bresler, A.·Bennaceur-Griscelli, A.·Chomel, J. C.·Turhan, A. G.

View original source ↗Export metadata ↓

Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the acquisition of BCR-ABL1 fusion in a hematopoietic stem cell. We identified the ENOX2 gene as up-regulated in BCR-ABL1-expressing UT-7 cell lines through a transcriptome assay. The oncofoetal ENOX2 protein (Ecto-Nicotinamide Adenine Dinucleotide Oxidase Disulfide Thiol Exchanger 2) is expressed on the external plasma membrane surface of cancer cells and can be released in cancer patients serum. Considering these data, we studied ENOX2 expression in CML cell lines and patients using quantitative RT-PCR, western-blots, the ELISA method, and transcriptomic dataset reanalysis. We confirmed increased ENOX2 mRNA expression in the BCR-ABL1-expressing UT-7 cell line. Comparable results were obtained in CML patients at diagnosis. Western-blot analyses on UT-7 and TET-inducible Ba/F3 cell lines established the up-regulation of ENOX2 protein. BCR-ABL1 has been found to induce ENOX2 overexpression in a kinase-dependent manner. In a series of 41 patients with CML, ELISA assays showed a highly significant increase of ENOX2 protein levels in the plasma of patients with CML (p < 0.0001) as compared to controls (n=28). Transcriptomic dataset (GSE4170) reanalyzes have shown specific ENOX2 mRNA overexpression in the chronic phase of the disease. Bioinformatic analyses identified several genes whose mRNA expression was positively correlated to ENOX2. Some of them encode proteins involved in cellular functions compatible with the growth deregulation observed in CML. All in all, our results demonstrate for the first time the upregulation of a secreted Redox protein in a BCR-ABL1-dependent manner in CML. Our data suggest that ENOX2 (through its transcriptional program) plays a significant role in the BCR-ABL1 leukemogenesis. Further studies are required to clarify the relationship between BCR-ABL1 and ENOX2.

Source connections

Published article ↗

Explore related subjects

cancer biology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Baykal Kose, S., Voldoire, M., Desterke, C., Sorel, N., Cayssials, E., Johnson-Ansah, H., Guerci-Bresler, A., Bennaceur-Griscelli, A., Chomel, J. C., Turhan, A. G.. 2021-01-24. ENOX2 NADH Oxidase: A BCR-ABL1-dependent cell surface and secreted redox protein in chronic myeloid leukemia (CML). https://doi.org/10.1101/2021.01.23.427819

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

The methionine cycle sustains the mesenchymal phenotype of tumor cells and drives PDA progression

Mesenchymal traits are associated with poor prognosis in Pancreatic Ductal Adenocarcinoma (PDA), but direct targeting of mesenchymal tumor cells remains a challenge. Metabolic profiling of tumor cells isolated from murine PDA and liver metastases (LM) revealed that LM rely more on the methionine cycle than does primary PDA. This metabolic shift was specifically associated with increased activation of the methionine cycle in mesenchymal tumor cells compared to differentiated tumor cells. We show that the targeting of the key enzyme of the methionine cycle S-adenosylhomocysteine hydrolase (SAHH) in mesenchymal cells lowers the levels of homocysteine (Hcy) and glutathione, resulting in reduced antioxidant capacity, deregulated intracellular calcium homeostasis, and ultimately loss of mesenchymal markers. Together, these events decrease cell proliferation and invasion, blunting the tumorigenic and metastatic potential of SAHH-deficient cells, eventually impeding tumor growth and progression of the metastatic disease. Clinically, the high expression of SAHH in patients with mesenchymal PDA is correlated with poor survival, positioning SAHH as a potential therapeutic target to impede the pro-metastatic, mesenchymal phenotype of PDA.

cancer biology↗

bioRxiv2026

Arrest-associated transcriptional programmes outweigh apoptosis-associated programmes in treatment-naive pancreatic ductal adenocarcinoma

Background: Pancreatic ductal adenocarcinoma (PDAC) is driven by mutant KRAS, and RAS inhibitors now extend survival in previously treated metastatic disease. Whether treatment shrinks a tumour or only halts its growth depends partly on whether cancer cells die or stop dividing, yet how untreated PDAC cells are balanced between these programmes is unknown. Aims: We aimed to characterise the balance between apoptosis-associated and arrest-associated transcriptional programmes in treatment-naive PDAC and to examine their relationships with tumour subtype, TGM2 expression, tissue organisation, survival and drug sensitivity. Methods and results: We scored 52,999 malignant cells from 18 untreated patients in the Hwang atlas using a transcriptional contrast between genes associated with apoptosis and genes associated with resistance to apoptosis or cell-cycle arrest. In every patient the contrast was shifted toward the arrest-associated side: using equality between the two sides as the dividing threshold, 86.3% of cells with an informative score fell on that side, although the proportion depends on the threshold chosen. The shift recurred in the independent Steele atlas (median 71.6% per sample, range 37.1% to 90.8%). In the discovery cohort, tumours with higher basal-like scores had fewer arrest-side cells, and TGM2 expression was modestly higher on the arrest-associated side in both cohorts. The contrast did not track cell-line drug sensitivity or survival in bulk tumours. Conclusion: Untreated PDAC cells show a reproducible transcriptional bias toward anti-apoptotic and cell-cycle-arrest programmes. Whether this bias predicts cellular responses to treatment remains to be tested.

cancer biology↗

bioRxiv2026

Quantitative live imaging reveals region-dependent medulloblastoma disseminationin the zebrafish brain

Medulloblastoma is the most common malignant pediatric brain tumor, and relapse is frequently driven by dissemination within the central nervous system. Yet the early dynamics of tumor spread remain difficult to resolve in vivo. Here, we orthotopically transplanted human medulloblastoma cells into larval zebrafish and followed individual xenografts by longitudinal high-resolution confocal imaging. ONS-76 showed particularly robust dissemination, with hindbrain tumors spreading into the developing cerebellum in 81.5% of larvae, more than fourfold the frequency observed for forebrain or midbrain tumors. Disseminating cells extended along brain-surface and leptomeningeal-like regions and frequently associated with cerebral vasculature. Quantitative analysis of tumor area, perimeter, compactness, convex hull area, and fractal dimension captured changes in growth and spatial complexity over time. Dasatinib reduced tumor expansion and dissemination-related features in a concentration-dependent manner, while higher doses revealed host toxicity. These findings establish a powerful in vivo model for resolving medulloblastoma dissemination and therapeutic response.

cancer biology↗