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

Abstract

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.

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 …”

“…NPM‐ALK is present in most ALK+ ALCLs, but translocation partners other than NPM are also known, and about 90% of pediatric and young adult cases are ALK positive . Oncogenic activity of NPM‐ALK is usually attributed to ALK, acting in large part through STAT3 signaling . NPM activity in ALCL is not well investigated.…”

“…3,13 Oncogenic activity of NPM-ALK is usually attributed to ALK, acting in large part through STAT3 signaling. 14,15 NPM activity in ALCL is not well investigated. ALK negative ALCL also occurs, predominantly in adults, and often involves STAT3 activation mediated in other ways than through ALK signaling.…”

Nucleophosmin-anaplastic lymphoma kinase: the ultimate oncogene and therapeutic target

“…73 In this review, we have summarized how NPM-ALK, a chimeric tyrosine kinase, induces most if not all of these oncogenic features (Figure 3). 74 Accordingly, NPM-ALK homodimerizes, autophosphorylates, and initiates signaling cascades that recapitulate IL-2-type progrowth cell signaling by modulating expression of protein-and miR-encoding genes, as well as by altering the functional status of intracellular proteins. NPM-ALK also protects cells from hypoxia and induces angiogenesis, deregulates DNA repair pathways, shifts cancer cell metabolism, and induces embryonic transcriptional programs that permit tissue evasion and metastasis.…”

Reversal of microRNA-150 silencing disadvantages crizotinib-resistant NPM-ALK(+) cell growth

“…ALK fusion proteins have also been reported in other cancers, including a proportion of non-small-cell lung cancers (NSCLC) and inflammatory myofibroblastic tumors (IMTs). The ALK fusion partners induce homodimerization, leading to constitutive ALK kinase domain (KD) activation (5). Aberrant ALK activation triggers various prosurvival signaling pathways whose main target is the STAT3 pathway and subsequent oncogenesis (3,5).…”