Stromal cell–mediated glycolytic switch in CLL cells involves Notch-c-Myc signaling

Jitschin, Regina; Braun, Martina; Qorraj, Mirjeta; Saul, Domenica; Blanc, Katarina Le; Zenz, Thorsten; Mougiakakos, Dimitrios

doi:10.1182/blood-2014-10-607036

Cited by 77 publications

(80 citation statements)

References 27 publications

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“…Primary lymphoma cells without MYC rearrangement could also survive in co-culture with CAF for a longer time than in monoculture (Supplemental Figure S1A). We next analyzed adenosine triphosphate (ATP) production in the tumor cells based on a previous finding that stromal cells induced an increase in ATP in tumor cells, resulting in cell proliferation and survival [22]. As expected, ATP increased in tumor cells that were co-cultured with CAF (Figure 1D).…”

Section: Resultsmentioning

confidence: 89%

“…As expected, ATP increased in tumor cells that were co-cultured with CAF (Figure 1D). Moreover, since the tumor environment promotes glycolysis resulting in energy production in tumor cells, [22] we analyzed the expression of key enzymes involved in glycolysis including hexokinase-2 (HK2), pyruvate dehydrogenase kinase-1 (PDK1), and lactate dehydrogenase A (LDHA) in the presence or absence of co-culture with CAF, using western blotting. Markedly increased expression of HK2 and PDK1 was observed when the cells were co-cultured with CAF (Figure 1E).…”

Section: Resultsmentioning

confidence: 99%

“…The tumor microenvironment has therefore drawn much attention as an attractive potential therapeutic target for intractable lymphoma [20, 21]. For example, it has been shown that stromal cells in the tumor microenvironment can promote a metabolic switch in malignant tumor cells away from mitochondrial respiration to glycolysis [22]. This so-called Warburg effect confers growth advantages and drug resistance to tumors [23].…”

Section: Introductionmentioning

confidence: 99%

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Emetine elicits apoptosis of intractable B-cell lymphoma cells with MYC rearrangement through inhibition of glycolytic metabolism

et al. 2016

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Despite improved clinical outcomes of diffuse large B-cell lymphoma, a certain proportion of patients still develop a primary refractory disease. To overcome these lymphomas that are intractable to existing treatment strategies, the tumor microenvironment has been identified as a potential therapeutic target. Here we describe our search for effective drugs for primary refractory lymphoma cells with MYC rearrangement. Through the drug screening of 3,440 known compounds, we identified a unique compound, emetine. This compound was effective against lymphoma cells with MYC rearrangement from two different patients that were co-cultured with cancer associated fibroblasts. Emetine induced the death of these cells with a half maximal inhibitory concentration of 312 nM and 506 nM, respectively. Subsequent analyses of the mechanism of action of emetine showed that the drug induced apoptosis of tumor cells via alteration of glucose metabolism through inhibition of hypoxia inducible factor-1α. Moreover, emetine inhibited the potential of cancer associated fibroblasts to support tumor cell viability in vitro and demonstrated significant inhibition of tumor growth in in vivo analyses. Emetine also induced cell death in other primary refractory lymphoma cells with MYC rearrangement. Our combined data indicate that emetine is a potential promising drug for the treatment of intractable lymphomas, which targets both the tumor and its microenvironment.

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Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Emetine elicits apoptosis of intractable B-cell lymphoma cells with MYC rearrangement through inhibition of glycolytic metabolism

et al. 2016

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“…A mechanism of this protective effect of the microenvironment appears to be mediated via an adaptation to oxidative stress with decreased mitochondrial electron transfer 12 and a switch to glycolysis. 19 In this study, we show that the reprogrammed stromal cells generate an excess of lactate, which is released into the extracellular fluid. We speculate that this lactate is used preferentially by tumor cells as a source of energy, a process we have previously termed the reverse Warburg effect.…”

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confidence: 65%

Metabolic reprogramming of bone marrow stromal cells by leukemic extracellular vesicles in acute lymphoblastic leukemia

Johnson

Dempsey

Chadwick

et al. 2016

Blood

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Cancer cells produce unique heterogeneous vesicles 1 capable of transferring oncogenic material 2,3 to other cells, 4,5 with the potential of modulating a tumor-supportive environment. [6][7][8] We have previously reported the presence of lipid-enriched, membrane-bound subcellular vesicles at the periphery of acute lymphoblastic leukemia (ALL) cell lines. 9,10 We now extend these findings to describe heterogeneous anucleate vesicles released into extracellular fluids in vitro and in vivo by primary B-cell precursor (BCP) ALL blasts and cell lines. Leukemic extracellular vesicles (LEVs) were internalized by stromal cells, and induced a metabolic switch.Extracellular vesicles (EVs) are enclosed in lipid bilayers originating from the cell of origin, released by both normal and cancer cells.1 Here, the BCP cell-specific membrane protein CD19 present within membrane lipid rafts 11 was used to identify the cell of origin of EVs in clinical samples. We directly compared plasma samples from CD19 1 primary BCP-ALL bone marrow aspirates at diagnosis containing .95% malignant blasts with matched remission samples obtained after 28 days of therapy ( Figure 1A LEVs ( Figure 1E). The effect of LEV internalization by BMSCs was investigated in the human mesenchymal stem cell line HS5 14 exposed to LEVs released by the BCP-ALL cell lines SD1 and NALM6. Proliferation and viability assays revealed no significant differences from control ( Figure 2A). Despite a sustained increase in AKT phosphorylation over 24 hours ( Figure 2B), nonsignificant reductions in adenosine triphosphate (ATP) concentrations were observed ( Figure 2C). Next, the 2 major energyproducing pathways of the cell and parameters of metabolism were assessed. At 24 hours, HS5 1 LEVs showed a reduced oxygen consumption rate (OCR) compared with control, were less sensitive to the inhibition of ATP by oligomycin, and did not change OCR when electron transport from ATP generation in the mitochondria was uncoupled ( Figure 2D). Disrupting the electron transport chain (rotenone/antimycin A) reduced OCR to a comparable level in all cells, suggesting that the rate of oxygen consumption from nonmitochondrial sources was comparable. HS5 1 LEV have a significantly reduced spare respiratory capacity, an indicator of a decreased ability to respond to stress or metabolic challenge ( Figure 2D). Overall, these results suggest that uptake of LEVs significantly reduced mitochondrial respiration in recipient stromal cells.In the absence of glucose, HS5 and HS5 1 LEVs had comparable extracellular acidification rates (ECARs) ( Figure 2E). In the presence of glucose, HS5 1 LEVs initiated a sharp increase in ECAR compared with control (;fivefold), suggesting a higher glycolytic rate. Inhibiting ATP synthase increased ECAR in both HS5 1 LEVs and controls, but more sharply in the latter. Following the addition of 2-deoxy-D-glucose, a competitive inhibitor of glycolysis, ECARs returned to base levels in both control and LEV-exposed cells. Thus, in the presence of glucose, LEV-exposed HS5 s...

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“…In this issue of Blood, Martelli et al 1 and El Hajj et al 2 independently report that nucleophosmin-1 (NPM1)-mutant leukemia is particularly vulnerable to a novel strategy combining all-trans retinoic acid (ATRA) with arsenic trioxide (ATO). The era of targeted therapy has seen some of its greatest successes in the hematologic arena (eg, breakpoint cluster region [BCR]/Abelson [ABL] kinase inhibitors in chronic myeloblastic leukemia and ATRA in acute promyelocytic leukemia [APL]).…”

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confidence: 99%

ATRA and ATO team up against NPM1

Grant

2015

Blood

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Stromal cell–mediated glycolytic switch in CLL cells involves Notch-c-Myc signaling

Abstract: Key Points Stromal cells promote a glycolytic switch in CLL cells in a Notch-c-Myc signaling-dependent manner. Targeting glucose metabolism or the Notch-c-Myc signaling pathway could be exploited to breach stromal cell–mediated CLL drug resistance.

Cited by 77 publications

References 27 publications

Emetine elicits apoptosis of intractable B-cell lymphoma cells with MYC rearrangement through inhibition of glycolytic metabolism

Emetine elicits apoptosis of intractable B-cell lymphoma cells with MYC rearrangement through inhibition of glycolytic metabolism

Metabolic reprogramming of bone marrow stromal cells by leukemic extracellular vesicles in acute lymphoblastic leukemia

ATRA and ATO team up against NPM1

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