The enzymatic activity of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase is enhanced by NPM-ALK: new insights in ALK-mediated pathogenesis and the treatment of ALCL

Boccalatte, Francesco; Voena, Claudia; Riganti, Chiara; Bosìa, Amalia; D’Amico, Lucia; Riera, Ludovica; Cheng, Mangeng; Ruggeri, Bruce; Jensen, Ole N.; Goss, Valerie L.; Lee, Kimberly; Nardone, Julie; Rush, A. John; Polakiewicz, Roberto D.; Comb, Michael J.; Chiarle, Roberto; Inghirami, Giorgio

doi:10.1182/blood-2008-06-161018

Cited by 44 publications

(43 citation statements)

References 43 publications

(71 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The underlying mechanism has not been clearly determined, but it was recently demonstrated that certain enzymes, which catalyze purine biosynthesis, are increased by ALK-mediated phosphorylation. Therefore, ALK-positive tumors may be more susceptible to antifolate agents (9).…”

Section: Discussionmentioning

confidence: 99%

Marked tumor response to crizotinib after 4 years of maintenance pemetrexed in a patient with anaplastic lymphoma kinase-positive non-small-cell lung cancer

Zhang

Huang

et al. 2014

Molecular and Clinical Oncology

View full text Add to dashboard Cite

Abstract. Maintenance therapy with pemetrexed is well tolerated and achieves prolonged progression-free and overall survival in patients with advanced lung adenocarcinoma. The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) is a recently identified fusion oncogene that exists in ~5% of non-small-cell lung cancers (NSCLCs). It was demonstrated that ALK-positive NSCLCs exhibit a high response rate to the ALK inhibitor crizotinib. This is the case report of a patient with NSCLC harboring EML4-ALK rearrangement, who experienced slowly progressive disease within 4 years of maintenance treatment with pemetrexed and later exhibited a marked response to crizotinib. The sustained clinical benefits suggest further investigations on anticancer agent administration.

show abstract

Section: Discussionmentioning

confidence: 99%

Marked tumor response to crizotinib after 4 years of maintenance pemetrexed in a patient with anaplastic lymphoma kinase-positive non-small-cell lung cancer

Zhang

Huang

et al. 2014

Molecular and Clinical Oncology

View full text Add to dashboard Cite

show abstract

“…Because NPM-ALK is known to interact with other proteins primarily through its phosphorylated tyrosine residues, we hypothesized that mutation (ie, replaced by phenylalanine) of the one of the tyrosine residues involved in phosphorylation may decrease the NPM-ALK·MSH2 binding. Of the eight tyrosine residues that are outside the kinase activation loop of ALK and are known to be involved in phosphorylation, 31,39 only NPM-ALK Y191 showed an appreciable (60% reduction by densitometry) decrease in the NPM-ALK·MSH2 interaction ( Figure 3A). NPM-ALK Y191 has not been identified as contributing to any previously reported NPM-ALK activated signaling pathway, thus minimizing the contribution of off-target effects, and the Y191F mutation does not result in reduced NPM-ALK conferred growth advantage.…”

Section: Interference Of Npm-alk·msh2 Binding Restores Mmr Functionmentioning

confidence: 99%

Fusion Tyrosine Kinase NPM-ALK Deregulates MSH2 and Suppresses DNA Mismatch Repair Function

Young

Bone

Wang

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

The fusion tyrosine kinase NPM-ALK is central to the pathogenesis of ALK-positive anaplastic large cell lymphoma (ALK ؉ ALCL). We recently identified that MSH2, a key DNA mismatch repair (MMR) protein integral to the suppression of tumorigenesis, is an NPM-ALK-interacting protein. In this study, we found in vitro evidence that enforced expression of NPM-ALK in HEK293 cells suppressed MMR function. Correlating with these findings, six of nine ALK ؉ ALCL tumors displayed evidence of microsatellite instability, as opposed to none of the eight normal DNA control samples (P ‫؍‬ 0.007, Student's t-test). Using co-immunoprecipitation, we found that increasing levels of NPM-ALK expression in HEK293 cells resulted in decreased levels of MSH6 bound to MSH2, whereas MSH2·NPM-ALK binding was increased. The NPM-ALK·MSH2 interaction was dependent on the activation/autophosphorylation of NPM-ALK, and the Y191 residue of NPM-ALK was a crucial site for this interaction and NPM-ALK-mediated MMR suppression. MSH2 was found to be tyrosine phosphorylated in the presence of NPM-ALK. Finally, NPM-ALK impeded the expected DNA damage-induced translocation of MSH2 out of the cytoplasm. To conclude, our data support a model in which the suppression of MMR by NPM-ALK is attributed to its ability to interfere with normal MSH2 biochemistry and function.

show abstract

“…Mass spectrometry data have also revealed an interaction between NPM-ALK and various heat shock proteins (Hsps) [Crockett et al 2004;Boccalatte et al 2009;Wu et al 2009]. Most studies regarding Hsps in the context of NPM-ALK pathobiology have been focused on Hsp90, which is a molecular chaperone that plays a critical role in helping proteins, termed clients, fold correctly.…”

Section: Mass Spectrometry Studies: Identifying Novel Pathways That Mmentioning

confidence: 99%

“…To that end, mass spectrometry studies were performed by several laboratories, including ours, focusing on the phosphoproteomic changes induced by NPM-ALK [Rush et al 2005;Boccalatte et al 2009;Wu et al 2010]. In order to optimize the sensitivity and specificity of our assay, we employed an approach combining sequential affinity purification of phosphopeptides and liquid chromatography-tandem mass spectrometry.…”

Section: Mass Spectrometry Studies: Identifying Novel Pathways That Mmentioning

confidence: 99%

The pathobiology of the oncogenic tyrosine kinase NPM-ALK: a brief update

Lai

Ingham

2013

Therapeutic Advances in Hematology

View full text Add to dashboard Cite

Extensive research has been carried out in the past two decades to study the pathobiology of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), which is an oncogenic fusion protein found exclusively in a specific type of T-cell lymphoid malignancy, namely ALKpositive anaplastic large cell lymphoma. Results from these studies have provided highly useful insights into the mechanisms by which a constitutively tyrosine kinase, such as NPM-ALK, promotes tumorigenesis. Several previous publications have comprehensively summarized the advances in this field. In this review, we provide readers with a brief update on specific areas of NPM-ALK pathobiology. In the first part, the NPM-ALK/signal transducer and activator of transcription 3 (STAT3) signaling axis is discussed, with an emphasis on the existence of multiple biochemical defects that have been shown to amplify the oncogenic effects of this signaling axis. Specifically, findings regarding JAK3, SHP1 and the stimulatory effects of several cytokines including interleukin (IL)-9, IL-21 and IL-22 are summarized. New concepts stemming from recent observations regarding the functional interactions among the NPM-ALK/STAT3 axis, β catenin and glycogen synthase kinase 3β will be postulated. Lastly, new mechanisms by which the NPM-ALK/STAT3 axis promotes tumorigenesis, such as its modulations of Twist1, hypoxiainduced factor 1α, CD274, will be described. In the second part, we summarize recent data generated by mass spectrometry studies of NPM-ALK, and use MSH2 and heat shock proteins as examples to illustrate the use of mass spectrometry data in stimulating new research in this field. In the third part, the evolving field of microRNA in the context of NPM-ALK biology is discussed.

show abstract

The enzymatic activity of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase is enhanced by NPM-ALK: new insights in ALK-mediated pathogenesis and the treatment of ALCL

Cited by 44 publications

References 43 publications

Marked tumor response to crizotinib after 4 years of maintenance pemetrexed in a patient with anaplastic lymphoma kinase-positive non-small-cell lung cancer

Marked tumor response to crizotinib after 4 years of maintenance pemetrexed in a patient with anaplastic lymphoma kinase-positive non-small-cell lung cancer

Fusion Tyrosine Kinase NPM-ALK Deregulates MSH2 and Suppresses DNA Mismatch Repair Function

The pathobiology of the oncogenic tyrosine kinase NPM-ALK: a brief update

Contact Info

Product

Resources

About