Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)⁺and ALK⁻anaplastic large-cell lymphoma

Abstract

Aberrant anaplastic lymphoma kinase (ALK) expression is a defining feature of many human cancers and was identified first in anaplastic large-cell lymphoma (ALCL), an aggressive non-Hodgkin T-cell lymphoma. Since that time, many studies have set out to identify the mechanisms used by aberrant ALK toward tumorigenesis. We have identified a distinct profile of micro-RNAs (miRNAs) that characterize ALCL; furthermore, this profile distinguishes ALK + from ALK − subtypes, and thus points toward potential mechanisms of tumorigenesis induced by aberrant ALK. Using a nucleophosmin-ALK transgenic mouse model as well as human primary ALCL tumor tissues and human ALCL-derived cell lines, we reveal a set of overlapping deregulated miRNAs that might be implicated in the development and progression of ALCL. Importantly, ALK + and ALK − ALCL could be distinguished by a distinct profile of "oncomirs": Five members of the miR-17-92 cluster were expressed more highly in ALK + ALCL, whereas miR-155 was expressed more than 10-fold higher in ALK − ALCL. Moreover, miR-101 was down-regulated in all ALCL model systems, but its forced expression attenuated cell proliferation only in ALK + and not in ALK − cell lines, perhaps suggesting different modes of ALK-dependent regulation of its target proteins. Furthermore, inhibition of mTOR, which is targeted by miR-101, led to reduced tumor growth in engrafted ALCL mouse models. In addition to future therapeutical and diagnostic applications, it will be of interest to study the physiological implications and prognostic value of the identified miRNA profiles.micro-RNA | mTOR | miR-155 | miR-101

18F-FDG PET in Patients with Primary Systemic Anaplastic Large Cell Lymphoma: Differential Features According to Expression of Anaplastic Lymphoma Kinase

“…ALK-positive patients were significantly younger than ALK-negative patients, being consistent with the established correlation between ALK expression and young age [7][8][9][10].…”

“…Together these findings support the view that primary systemic ALK-positive and ALK-negative ALCL are different disease entities [7][8][9][10].…”

“…Other studies also have demonstrated the differential expression of apoptotic proteins and micro-RNAs according to the ALK expression [9,10]. Although there have been many advances regarding the clinical, pathological and molecular characterization of primary systemic ALCL with differential characteristics according to the ALK expression, little is known regarding the role of 18 F-FDG PET in primary systemic ALCL.…”

New molecular insights into peripheral T cell lymphomas

“…Importantly, it was also reported that low expression of miR29a, probably achieved through methylation-mediated repression, appeared to play an important regulatory role in MCL-1 overexpression, promoting tumor cell survival by inhibiting apoptosis. Consistently, forced miR29a expression was found to modulate apoptosis through inhibition of MCL-1 expression with concomitant tumor growth reduction in vivo (64).…”

“…Fourth, the role of micro-RNAs (miRNAs) has so far been investigated mainly in ALCL. In particular, Merkel et al (64) reported that five members of the miR17-92 cluster were expressed more highly in ALK + ALCL, whereas expression levels of miR155 were more than 10-fold higher in ALK -ALCL. Moreover, miR101 is downregulated in all types of ALCL, a fact of potential therapeutic interest because mTOR is the target of this miRNA.…”