The Hematopoietic Oxidase NOX2 Regulates Self-Renewal of Leukemic Stem Cells

Adane, Biniam; Ye, Haobin; Khan, Nabilah; Pei, Shanshan; Minhajuddin, Mohammad; Stevens, Brett M.; Jones, Courtney L.; D’Alessandro, Angelo; Reisz, Julie A.; Zaberezhnyy, Vadym; Gasparetto, Maura; Ho, Tzu‐Chieh; Kelly, Kathleen; Myers, Jason R.; Ashton, John M.; Siegenthaler, Julie A.; Kume, Tsutomu; Campbell, Eric L.; Pollyea, Daniel A.; Becker, Michael W.; Jordan, Craig T.

doi:10.1016/j.celrep.2019.03.009

Cited by 70 publications

(95 citation statements)

References 54 publications

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“…High reactive oxygen species (ROS) levels in bulk CML and AML cells, compared to normal haematopoietic cells, are often explained through the actions of oncogenic kinases like BCR-ABL1, FLT3 or KRAS, which increase the activities of RAC GTPases, 67,68 or the actions of of membrane-bound NADPH oxidases, 69,70 which correlate with increased dependence of leukemic cells on mitochondrial respiration 71,72 . However, extremes in ROS levels (too high or too low) present problems to LSCs, as these extremes can promote differentiation and impair stem cell function 69,73 35,[87][88][89] . The exception to this appears to be MLL (also known as KMT2A)-rearranged AML, where LSCs possess similarities to an mRNA signature from embryonic stem cells 40 .…”

Section: [H2] Cell Surface Marker Definitions the Expression Of Cd34mentioning

confidence: 99%

The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML

2020

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For two decades, leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) have been advanced paradigms for the cancer stem cell field. In CML, the acquisition of the fusion tyrosine kinase BCR-ABL1 in a hematopoietic stem cell (HSC) drives its transformation to become a LSC. In AML, LSCs can arise from multiple cell types through the activity of a number of oncogenic drivers and pre-leukemic events-adding further layers of context and genetic and cellular heterogeneity to AML LSCs that is not observed in most cases of CML. Furthermore, LSCs from both AML and CML can be refractory to standardof-care therapies and persist in patients, diversify clonally, and serve as reservoirs to drive relapse, recurrence or progression to more aggressive forms. Despite these complexities, LSCs in both diseases share biological features, making them distinct from other CML or AML progenitor cells and from normal HSCs. These features may represent Achilles' heels against which novel therapies can be developed. Here, we

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Section: [H2] Cell Surface Marker Definitions the Expression Of Cd34mentioning

confidence: 99%

The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML

2020

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“…Enrichment of oxidative phosphorylation pathway ( Fig.2A) Research. and increasing cycling of liver leukemia cells may result in an increased ROS level (33).…”

Section: Endogenous Lipg Is Critical For Proliferation and Chemo-resimentioning

confidence: 99%

The Hepatic Microenvironment Uniquely Protects Leukemia Cells through Induction of Growth and Survival Pathways Mediated by LIPG

Minhajuddin

Krug

et al. 2021

Cancer Discovery

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Due to the disseminated nature of leukemia, malignant cells are exposed to many different tissue microenvironments, including a variety of extramedullary sites. In the present study, we demonstrate that leukemic cells residing in the liver display unique biological properties, and also contribute to systemic changes that influence physiological responses to chemotherapy. Specifically, the liver microenvironment induces metabolic adaptations via up-regulating expression of endothelial lipase (LIPG) in leukemia cells, which not only stimulates tumor cell proliferation through polyunsaturated fatty acid (PUFA) mediated pathways, but also promotes survival by stabilizing anti-apoptotic proteins. Additionally, hepatic infiltration and tissue damage caused by malignant cells induces release of liver-derived enzymes capable of degrading chemotherapy drugs, an event which further protects leukemia cells from conventional therapies. Together, these studies demonstrate a unique role for liver in modulating the pathogenesis of leukemic disease and suggest that the hepatic microenvironment may protect leukemia cells from chemotherapeutic challenge. SIGNIFICANCE The studies presented herein demonstrate that the liver provides a microenvironment in which leukemia cells acquire unique metabolic properties. The adaptations that occur in the liver confer increased resistance to chemotherapy. Therefore, we propose that therapies designed to overcome liver-specific metabolic changes will yield improved outcomes for leukemia patients. Research.

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“…In fact, AML proliferation is accompanied by NOX2-dependent extracellular ROS production in more than 60% of AML patients [ 10 ]. Studies have shown that fms-like tyrosine kinase 3—internal tandem repeat (FLT3-ITD) signaling involved NOX4 activity [ 15 ], while others demonstrated that NOX2 is implicated in leukemic development [ 11 , 16 , 17 , 18 ]. In addition, NOX-dependent ROS production has been shown to trigger mitochondrial transfer from BM stromal cells to AML blasts, thus fueling AML proliferation [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

VAS3947 Induces UPR-Mediated Apoptosis through Cysteine Thiol Alkylation in AML Cell Lines

Dor

Dakik

Polomski

et al. 2020

IJMS

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Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) involvement has been established in the oncogenic cell signaling of acute myeloid leukemia (AML) cells and in the crosstalk with their niche. We have shown an expression of NOX subunits in AML cell lines while NOX activity is lacking in the absence of exogenous stimulation. Here, we used AML cell lines as models to investigate the specificity of VAS3947, a current NOX inhibitor. Results demonstrated that VAS3947 induces apoptosis in AML cells independently of its anti-NOX activity. High-performance liquid chromatography (HPLC) and mass spectrometry analyses revealed that VAS3947 thiol alkylates cysteine residues of glutathione (GSH), while also interacting with proteins. Remarkably, VAS3947 decreased detectable GSH in the MV-4-11 cell line, thereby suggesting possible oxidative stress induction. However, a decrease in both cytoplasmic and mitochondrial reactive oxygen species (ROS) levels was observed by flow cytometry without disturbance of mitochondrial mass and membrane potential. Thus, assuming the consequences of VAS3947 treatment on protein structure, we examined its impact on endoplasmic reticulum (ER) stress. An acute unfolded protein response (UPR) was triggered shortly after VAS3947 exposure, through the activation of inositol-requiring enzyme 1α (IRE1α) and PKR-like endoplasmic reticulum kinase (PERK) pathways. Overall, VAS3947 induces apoptosis independently of anti-NOX activity, via UPR activation, mainly due to aggregation and misfolding of proteins.

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The Hematopoietic Oxidase NOX2 Regulates Self-Renewal of Leukemic Stem Cells

Cited by 70 publications

References 54 publications

The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML

The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML

The Hepatic Microenvironment Uniquely Protects Leukemia Cells through Induction of Growth and Survival Pathways Mediated by LIPG

VAS3947 Induces UPR-Mediated Apoptosis through Cysteine Thiol Alkylation in AML Cell Lines

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