Prognostic significance and therapeutic potential of the activation of anaplastic lymphoma kinase/protein kinase B/mammalian target of rapamycin signaling pathway in anaplastic large cell lymphoma

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.

Crizotinib induces apoptosis and gene expression changes in ALK+ anaplastic large cell lymphoma cell lines; brentuximab synergizes and doxorubicin antagonizes

“…These include IL6/JAK/STAT, particularly involving STAT3, as well as PI3K/Akt, phospholipase C gamma (PLC‐γ), RAS/MAPK, WNT/β catenin, mTOR, and TNF pathways. It also includes regulatory factors MYC, SHP1, MCL‐1, C/EBPβ, JunB, NfKappaB, heat shock proteins, histone deacetylation, and miRNAs . The sum of these activities appears to result in cell cycle progression and the inhibition of apoptosis, since ALK inhibitors result in G1‐S cell cycle arrest and apoptosis in cell line studies …”

“…It also includes regulatory factors MYC, SHP1, MCL-1, C/EBP , JunB, NfKappaB, heat shock proteins, histone deacetylation, and miRNAs. 14,[37][38][39][40][41][42][43][44] The sum of these activities appears to result in cell cycle progression and the inhibition of apoptosis, since ALK inhibitors result in G1-S cell cycle arrest and apoptosis in cell line studies. 24,45 In our current study, this concept is validated in that most of the genes annotated to ALCL were significantly down-regulated by crizotinib in what appears to be a tightly connected set of interactions resulting in apoptosis and cell cycle arrest.…”

Detection of an ALK Fusion in Colorectal Carcinoma by Hybrid Capture-Based Assay of Circulating Tumor DNA

“…Oncogenic ALK leads to the initiation of a number of downstream signaling cascades, including the STAT3 , AKT , and MAPK pathways (Fig. ).…”

Molecular genetics of childhood, adolescent and young adult non‐Hodgkin lymphoma

“…However, fusion proteins re‐localize ALK to either the cytoplasm or other intracellular compartments, with the fusion partner promoting constitutive activation via dimerization or by other mechanisms. Many effectors downstream of ALK have now been identified, including the RAS/ERK, PI3K/AKT, and JAK3/STAT3 pathways, and their contribution to ALCL biology is beginning to come into focus (Lamant et al , ; Vega et al , ; Chiarle et al , ; Li & Morris, ; Gao et al , ; Boi et al , ).…”

“…RAS/ERK and PI3K/AKT both stimulate the serine/threonine kinase mTOR, thereby promoting phosphorylation of mTOR substrates, which then promote growth and cell‐cycle progression (Vega et al , ; Chiarle et al , ; Li & Morris, ; Gao et al , ). ALK targets also enhance survival of ALCL cells.…”