Integrated phosphoproteomic and metabolomic profiling reveals NPM-ALK–mediated phosphorylation of PKM2 and metabolic reprogramming in anaplastic large cell lymphoma

McDonnell, Scott R.; Hwang, Steven R; Rolland, Delphine C.M.; Murga‐Zamalloa, Carlos; Basrur, Venkatesha; Conlon, Kevin; Fermin, Damian; Wolfe, Thomas; Raskind, Alexander; Ruan, Chunhai; Jiang, Jian Kang; Thomas, Craig J.; Hogaboam, Cory M.; Burant, Charles F.; Elenitoba-Johnson, Kojo S.J.; Lim, Megan S.

doi:10.1182/blood-2013-01-482026

Cited by 66 publications

(62 citation statements)

References 37 publications

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“…15 NPM-ALK, another form of ALK arrangement in anaplastic large cell lymphoma (ALCL), has been recently shown to phosphorylate pyruvate kinase M2 (PKM2), leading to inhibition of the enzyme activity and prevention of oxidative phosphorylation. 16 Therefore we examined whether EML4-ALK is linked to upregulation of glucose metabolism in ALK-rearranged NSCLC. To this end, we took advantage of two well-defined NSCLC cell lines H3122 and H2228 known to harbor variant 1 and variant 3 of EML4-ALK, respectively.…”

Section: Resultsmentioning

confidence: 99%

A causal link from ALK to hexokinase II overexpression and hyperactive glycolysis in EML4-ALK-positive lung cancer

Mohamed

et al. 2016

Oncogene

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A high rate of aerobic glycolysis is a hallmark of malignant transformation. Accumulating evidence suggests that diverse regulatory mechanisms mediate this cancer-associated metabolic change seen in a wide spectrum of cancer. The echinoderm microtubule associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion protein is found in approximately 3-7% of non-small cell lung carcinomas (NSCLC). Molecular evidence and therapeutic effectiveness of FDA-approved ALK inhibitors indicated that EML4-ALK is a driving factor of lung tumorigenesis. A recent clinical study showed that NSCLC harboring EML4-ALK rearrangements displayed higher glucose metabolism compared to EML4-ALK-negative NSCLC. In the current work, we presented evidence that EML4-ALK is coupled to overexpression of hexokinase II (HK2), one of the rate-limiting enzymes of the glycolytic pathway. The link from EML4-ALK to HK2 upregulation is essential for a high rate of glycolysis and proliferation of EML4-ALK-rearranged NSCLC cells. We identified hypoxia-inducible factor 1α (HIF1α) as a key transcription factor to drive HK2 gene expression in normoxia in these cells. EML4-ALK induced hypoxia-independent but glucose-dependent accumulation of HIF1α protein via both transcriptional activation of HIF1α mRNA and the PI3K-AKT pathway to enhance HIF1α protein synthesis. The EML4-ALK-mediated upregulation of HIF1α, HK2 and glycolytic metabolism was also highly active in vivo as demonstrated by FDG-PET imaging of xenografts grown from EML4-ALK-positive NSCLC cells. Our data reveal a novel EML4-ALK-HIF1α-HK2 cascade to enhance glucose metabolism in EML4-ALK-positive NSCLC.

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Section: Resultsmentioning

confidence: 99%

A causal link from ALK to hexokinase II overexpression and hyperactive glycolysis in EML4-ALK-positive lung cancer

Mohamed

et al. 2016

Oncogene

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“…The detailed methods were described in McDonnell et al (2013). Briefly, frozen cell cultures were homogenized in water, volumes were adjusted based on protein concentration in the extract, and proteins were precipitated by ethanol containing recovery standards.…”

Section: Methodsmentioning

confidence: 99%

Cell culture-based profiling across mammals reveals DNA repair and metabolism as determinants of species longevity

Upneja

Gałecki

et al. 2016

eLife

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Mammalian lifespan differs by >100 fold, but the mechanisms associated with such longevity differences are not understood. Here, we conducted a study on primary skin fibroblasts isolated from 16 species of mammals and maintained under identical cell culture conditions. We developed a pipeline for obtaining species-specific ortholog sequences, profiled gene expression by RNA-seq and small molecules by metabolite profiling, and identified genes and metabolites correlating with species longevity. Cells from longer lived species up-regulated genes involved in DNA repair and glucose metabolism, down-regulated proteolysis and protein transport, and showed high levels of amino acids but low levels of lysophosphatidylcholine and lysophosphatidylethanolamine. The amino acid patterns were recapitulated by further analyses of primate and bird fibroblasts. The study suggests that fibroblast profiling captures differences in longevity across mammals at the level of global gene expression and metabolite levels and reveals pathways that define these differences.DOI: http://dx.doi.org/10.7554/eLife.19130.001

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“…R2 and R2* are both more accurate than liver biopsy for determining response to iron chelation therapy[41]. However, it is important to use the same technique when tracking patients over time [42].…”

Section: Measurement Of Liver Iron Concentration (Lic)mentioning

confidence: 99%

Use of Magnetic Resonance Imaging to Monitor Iron Overload

Wood

2014

Hematology/Oncology Clinics of North America

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SYNOPSIS Treatment of iron overload requires robust estimates of total body iron burden and its response to iron chelation therapy. Compliance with chelation therapy varies considerably among patients and individual reporting is notoriously unreliable. Even with perfect compliance, intersubject variability in chelator effectiveness is extremely high, necessitating reliable iron estimates to guide dose titration. In addition, each chelator has a unique profile with respect to clearing iron stores from different organs. This chapter will present the tools available to clinicians monitoring their patients, focusing on non-invasive magnetic resonance imaging methods because they have become the de-facto standard of care.

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Integrated phosphoproteomic and metabolomic profiling reveals NPM-ALK–mediated phosphorylation of PKM2 and metabolic reprogramming in anaplastic large cell lymphoma

Cited by 66 publications

References 37 publications

A causal link from ALK to hexokinase II overexpression and hyperactive glycolysis in EML4-ALK-positive lung cancer

A causal link from ALK to hexokinase II overexpression and hyperactive glycolysis in EML4-ALK-positive lung cancer

Cell culture-based profiling across mammals reveals DNA repair and metabolism as determinants of species longevity

Use of Magnetic Resonance Imaging to Monitor Iron Overload

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