Abstract
BackgroudActivation of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway has been demonstrated to be involved in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-mediated tumorigenesis in anaplastic large cell lymphoma (ALCL) and correlated with unfavorable outcome in certain types of other cancers. However, the prognostic value of AKT/mTOR activation in ALCL remains to be fully elucidated. In the present study, we aim to address this question from a clinical perspective by comparing the expressions of the AKT/mTOR signaling molecules in ALCL patients and exploring the therapeutic significance of targeting the AKT/mTOR pathway in ALCL.MethodsA cohort of 103 patients with ALCL was enrolled in the study. Expression of ALK fusion proteins and the AKT/mTOR signaling phosphoproteins was studied by immunohistochemical (IHC) staining. The pathogenic role of ALK fusion proteins and the therapeutic significance of targeting the ATK/mTOR signaling pathway were further investigated in vitro study with an ALK + ALCL cell line and the NPM-ALK transformed BaF3 cells.ResultsALK expression was detected in 60% of ALCLs, of which 79% exhibited the presence of NPM-ALK, whereas the remaining 21% expressed variant-ALK fusions. Phosphorylation of AKT, mTOR, 4E-binding protein-1 (4E-BP1), and 70 kDa ribosomal protein S6 kinase polypeptide 1 (p70S6K1) was detected in 76%, 80%, 91%, and 93% of ALCL patients, respectively. Both phospho-AKT (p-AKT) and p-mTOR were correlated to ALK expression, and p-mTOR was closely correlated to p-AKT. Both p-4E-BP1 and p-p70S6K1 were correlated to p-mTOR, but were not correlated to the expression of ALK and p-AKT. Clinically, ALK + ALCL occurred more commonly in younger patients, and ALK + ALCL patients had a much better prognosis than ALK-ALCL cases. However, expression of p-AKT, p-mTOR, p-4E-BP1, or p-p70S6K1 did not have an impact on the clinical outcome. Overexpression of NPM-ALK in a nonmalignant murine pro-B lymphoid cell line, BaF3, induced the cells to become cytokine-independent and resistant to glucocorticoids (GCs). Targeting AKT/mTOR inhibited growth and triggered the apoptotic cell death of ALK + ALCL cells and NPM-ALK transformed BaF3 cells, and also reversed GC resistance induced by overexpression of NPM-ALK.ConclusionsOverexpression of ALK due to chromosomal translocations is seen in the majority of ALCL patients and endows them with a much better prognosis. The AKT/mTOR signaling pathway is highly activated in ALK + ALCL patients and targeting the AKT/mTOR signaling pathway might confer a great therapeutic potential in ALCL.
Highlights
Anaplastic large cell lymphoma (ALCL) is an aggressive form of non-Hodgkin’s lymphoma (NHL) of T/null lineage
Overexpression of anaplastic lymphoma kinase (ALK) due to chromosomal translocations is seen in the majority of ALCL patients and endows them with a much better prognosis
The Protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is highly activated in ALK + ALCL patients and targeting the AKT/mTOR signaling pathway might confer a great therapeutic potential in ALCL
Summary
Anaplastic large cell lymphoma (ALCL) is an aggressive form of non-Hodgkin’s lymphoma (NHL) of T/null lineage. It constitutes approximately 5% of all human NHL, but accounts for as many as 30% to 40% of pediatric large cell lymphomas [1]. 50 to 70% of ALCL patients carry characteristic chromosomal translocations involving the anaplastic lymphoma kinase (ALK) gene on chromosome 2p23, resulting in ALK overexpression due to the abnormal fusion of ALK with other genes [2]. ALK immunostainning of NPM-ALK-positive ALCL cases shows a characteristic cytoplasmic and nuclear distribution of the chimeric ALK protein that is due to heterooligomerization of NPM-ALK and normal NPM, a phosphoprotein that normally shuttles ribonucleoproteins between the cytoplasm and nucleus, but can aberrantly transport NPM-ALK to the nucleus [12]; whereas patients with the variant-ALK fusion proteins demonstrate cytoplasmic staining only [13,14]. Compared with ALK negative (ALK-) ALCL, ALK positive (ALK+) ALCL occurs more frequently in younger patients who respond well to chemotherapy and have a favorable clinical outcome [1,15,16,17,18,19]
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