Editorial
Mir-17-92 Cluster Dysregulation in Lymphoid Malignancies: Its Role in Limphomagenesis
Alejandro Roisman and Irma Slavutsky*
Laboratory of Genetics of Lymphoid Neoplasms, Institute of Experimental Medicine, Argentina
*Corresponding author: Irma Slavutsky, Laboratory of Genetics of Lymphoid Neoplasms, Institute of Experimental Medicine, Argentina
Published: 20 Feb, 2017
Cite this article as: Roisman A, Slavutsky I. Mir-
17-92 Cluster Dysregulation in
Lymphoid Malignancies: Its Role in
Limphomagenesis. Clin Oncol. 2017;
2: 1210.
Abstract
MicroRNAs (miRNAs) are short, endogenous singled-stranded noncoding RNAs whose dysregulation has been implicated in important biologic processes, including cancer development. The principal mechanism of action of these master regulators is to control gene expression by suppressing mRNA translation and reducing mRNA stability. In particular, the miR-17-92 cluster is one of the most frequently miRNA expressed in different subtypes of non-Hodgkin lymphomas. Its widespread dysregulation in these pathologies suggests this cluster as a new biomarker that may supplement lymphoma diagnosis and prognosis, and also as an attractive target to design novel strategies for cancer therapy.
Editorial
microRNAs (miRNAs) are small non-coding single-stranded RNAs of 17-25 nucleotides
in length that play central regulatory functions in gene expression and transcriptional control
by targeting mRNAs and triggering its degradation and/or translational interference [1]. They
are involved in important biologic processes, and its dysregulation has been associated with the
pathogenesis of several diseases including tumor development and maintenance [2]. Some miRNAs
are located in genomic regions involved in chromosomal alterations related to cancer and causally
implicated in oncogenesis, acting as tumor suppressor genes or oncogenes [3].
In this context, experimental data have demonstrated the oncogenic properties of miR17-92
polycistronic cluster in both hematological malignancies and solid tumors. This cluster is located
in a region of 800 bp in the non-protein-coding gene C13 or f25 at 13q31.3 (4) that encodes for
six distinct miRNAs (miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92a-1). They
constitute three families according to miRNA seed sequences: miR-17 (miR-17, miR-20a and miR-
18a), miR-19 (miR-19a and miR-19b-1), and miR-92. miR-17-92 cluster also presents two paralogs:
miR-106a-363 on chromosome X and miR-106b-25 on chromosome 7. All these miRNAs show
high sequence conservation across species suggesting evolutionary pressure to maintain such
organization [5]. As a strong oncogene, miR-17-92 regulates multiple cellular processes that favor
malignant transformation [6], mainly due to gene amplification and MYC-mediated transcriptional
upregulation [7,8]. Particularly, miR-17-92 drives lymphomagenesis by suppressing the expression
of multiple negative regulators of the PI3K (Phosphatidylinositide 3-kinase) and NF-κB (nuclear
factor kappa B) pathways, and by inhibiting apoptosis [8].
Specific miRNAs characterize various subtypes of Non-Hodgkin Lymphomas (NHLs) and
have essential roles in differentiation and lymphomagenesis. Among them, the miR-17-92 cluster is
the most frequently over-expressed in B-cell NHLs [9], including Diffuse Large B-cell Lymphoma
(DLBCL), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL) and Burkitt
Lymphoma (BL) [8].
In reference to MCL, different authors showed miR-17-92 cluster up regulation in this entity
[10,11]. Particularly, Navarro, et al. [10] found miR-17 and miR-20a over expression with high MYC
mRNA levels in tumors with a more aggressive clinical behavior, distinguishing two subgroups
of MCL patients with different miR expression profiles associated to biological features. More
recently, we have explored gene expression patterns of SOXC cluster and, miR17, miR18a, miR19b
and miR92a members of the miR17-92 cluster and evaluated their correlation with biological
and clinical characteristics of the disease [12]. Interestingly, unsupervised hierarchical clustering
analysis revealed two distinctive subsets of tumors showing significant differences in important
clinical variables: Cluster A associated with high expression of SOX11, SOX12, miR19a and miR92a
signature linked to more aggressive disease and short survival, and Cluster B with SOX4, miR17 and miR18a over expression, exhibiting a reduced proliferating signature
and a significantly better prognosis with longer overall survival. This
combined analysis of coding and non coding genes in MCL represent
a new approach that may contribute to improve the understanding
of this pathology. In addition, experimental studies showed that over
expression of miR-17-92 mediates chemo- and radioresistance and
enhances tumor growth in MCL cells, suggesting this cluster as a
potential therapeutic target for patients with this lymphoma [13,14].
Studies on CLL patients found increased miR17 expression
in unmutated and ZAP-70 positive cases [15]. Furthermore, a
diminished miR-17 activity was seen in patients with TP53 mutation/
deletion [16], results that agree with those observed by Li et al. [17]
that found low miR-17 and miR-20a and high miR-19a, miR-19b-1 and
miR-92a-1 mRNA levels in cases with TP53 alterations in comparison
with healthy donors. In addition, there are evidences of the induction
of miR-17-92 expression associated with MYC expression induced
by the micro environmental, supporting the impact of these stimuli
in miRNAs transcriptional regulation [18] as well as the interaction
between MYC and miR-17-92 cluster in CLL patients [15]. MYC is a
transcription factor that has a key role in promoting tumorigenesis
by activating and repressing target genes involved in many pathways
associated to malignant development, being one of the most common
abnormalities in cancer [19].
As known, DLBCL is the most common type of NHLs, showing
three different molecular subtypes with distinct genetic aberrations
and clinical outcome. Among them, the miR-17-92 cluster is
significantly upregulated in germinal center B-cell (GCB) subtype
compared to activated B-cell [20,21], whereas miR-17 is overexpressed
in DLBCL originated within the central nervous system [22]. GCBDLBCL
frequently shows amplifications at 13q31.3 region that could
be the cause of miR-17-92 upregulation [7]. This mechanism is also
observed in patients with Richter´s syndrome, in which 13q31.3
amplifications are observed at the time of transformation, associated
to the gain of MYC and loss of TP53, supporting the involvement
of the miR-17-92 cluster in the acquisition of a more biologically
aggressive disease [23]. MYC binds to the promoter of the miR-17-92
cluster and to the E2F1 promoter (a transcription factor that promotes
G1-to-S phase progression) activating their transcription, while the
miR-17-92 repress the expression of E2F1, indicating the presence of
a fine-tuned regulatory mechanism of proliferation [24]. In addition,
miR-17-92 cluster also impacts on B-Cell Receptor (BCR) signaling.
Microarray studies showed MYC and MIR17HG loci amplifications,
consistent with the high level of MYC and members of miR-17-92
cluster required for DLBCLs to sustain BCR response, suggesting a
lymphomagenic feed-forward regulatory loop in this pathology [25].
Consistent with those reported for other NHL subtypes, studies in
BL pediatric patients, an aggressive disease characterized by reciprocal
translocations of MYC with the immunoglobulin genes, found 13q31
amplification and higher levels of miR17, associated to a tendency for
early relapse, confirming the importance of MYC/miR17-92 axis in
lymphoma development [26,27].
Although the number miRNAs analysis in primary cutaneous
lymphomas is limited, some reports have evaluated the miR-17-
92 cluster expression. A recent study in primary cutaneous B-cell
lymphomas [28] found miR-106a (paralog), miR-20a and miR-20b
over expression as well as the down regulation of PTEN (Phosphatase
and tensin homolog) tumor suppressor gene associated to disease
progression. Interestingly, a new study of our group [29] in patients
with Mycosis Fungoides (MF), the most frequent Cutaneous
T-Cell Lymphoma (CTCL), found higher levels of miR17, miR18a,
miR19b and miR92a in patients compared to controls. The analysis
according to morphological subtypes showed miR17 and miR-18a
over expression in tumoral MF, meanwhile miR19b and mir92a
exhibited increased levels in folliculotropic and transformed MFs.
In addition, miRNA gene expression profiles showed that miR17
and miR19b were upregulated in patients with deletion of 9p21.3
(CDKN2A) and/or 8q24.21 (MYC) gains, providing new insights
in the comprehension of MF pathobiology. In line with our results,
Ralfkiaer, et al. [30] also found enhanced expression of miR-17-
92 paralogs, miR-106a/363 and miR-106b/25, in advanced disease
compared with early MF, suggesting a role for these miRs in disease
progression. Previous reports [31,32] showed that miR106b/25 is
also upregulated in Sézary Syndrome, a rare and aggressive variant
of CTCL, indicating a potential oncogenic function for this miR17-
92 paralog. In contrast Ballabio, et al. [33] found down regulation of
miR17, miR19a, miR92 and miR106a in this pathology, diminishing
apoptosis rates and enhancing proliferation. More studies will clarify
this discordant results.
Concluding, the present revision shows the important governing
roles of miR-17-92 cluster and its paralogs in lymphoid malignancies.
Their widespread dysregulation in these pathologies suggests they
may be considered as new biomarkers that may add new insights in
lymphoma diagnosis and prognosis, and also as attractive targets to
design novel strategies for cancer therapy.
Acknowledgement
This work was supported by grants from the National Research Council (CONICET) (PIP-2012-517), the National Agency of Scientific and Technical Promotion (ANPCyT) (PICT-2014-1566) and the National Cancer Institute.
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