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https://doi.org/10.1038/s41375-018-0036-x
REVIEW ARTICLE
Abstract
Multiple myeloma (MM) is a plasma cell tumor marked by clonal evolution and preceded by a premalignant stage, which
progresses via molecular pathway deregulation, including MYC activation. This activation relates to translocation or gain of
the MYC locus and deregulation of upstream pathways such as IRF4, DIS3/LIN28B/let-7, or MAPK. Precision medicine is
an approach to predict more accurately which treatment strategies for a particular disease will work in which groups of
patients, in contrast to a “one-size-fits-all” approach. The knowledge of mechanisms responsible for MYC deregulation in
MM enables identification of vulnerabilities and therapeutic targets in MYC-driven tumors. MYC can be targeted directly or
indirectly, by interacting with several of its functions in cancer. Several such therapeutic strategies are evaluated in clinical
1234567890();,:
trials in MM. In this review, we describe the mechanism of MYC activation in MM, the role of MYC in cancer progression,
and the therapeutic options to targeting MYC.
Introduction while the number of deaths was 3.3 per 100,000 people per
year [2]. MM evolves from a premalignant stage named
B-cell lymphoid tissues consist in the primary tissue (bone monoclonal gammopathy of undetermined significance
marrow), in which lymphoid precursors mature to a stage at (MGUS), followed by smoldering MM (SMM), to symp-
which they express antigen receptors, and the secondary tomatic myeloma [3, 4]. MYC deregulation is one of the key
lymphoid tissues (lymph nodes, spleen, and mucosa- features of disease progression. MYC alterations are pro-
associated lymphoid tissues), in which antigen presenta- posed to be a trigger of MGUS to MM transition [5], as well
tion and specific responses occur. These structures enable as a late genomic event responsible for tumor progression.
the development of the immunoglobulin (Ig) receptor- Precision medicine aims to predict more accurately
expressing B cells, including naive, germinal center (GC), which treatment and prevention strategies will work for
memory B cells, and plasma cells. At each of these stages, particular subgroups of patients. Recent development of
occurrence of molecular alterations can lead to the devel- high-throughput technologies led to an accumulation of
opment of lymphoid tumors. knowledge regarding the molecular drivers of MM tumors.
Multiple myeloma (MM) is a B-cell malignancy char- Implementing this molecular information to clinical practice
acterized by the accumulation of clonal plasma cells in the with goal of developing new therapeutic strategies still
bone marrow [1]. It accounts for approximately 13% of remains an important challenge for the scientific
hematologic cancers [1]. According to age-adjusted rates community.
based on 2009–2013 cases and deaths, the number of new MYC (v-myc myelocytomatosis viral oncogene homo-
cases of myeloma was 6.5 per 100,000 people per year, log, c-MYC) is an oncogenic protein, first described as a
cellular homolog of the avian retroviral oncogene v-myc in
1982 [6, 7]. It belongs to a family of three members: MYC,
* S. Manier NMYC, and LMYC located on chromosomes 8q24, 2p24,
salomon_manier@dfci.harvard.edu and 1p34, respectively [8–10]. MYC rearrangements in the
1
Ig locus were reported in BALB/c mouse plasmacytomas
IRCL, INSERM UMR-S1172, Univ. Lille, Lille, France
[11] and in most cases of Burkitt lymphoma [8]. MYC
2
Institute of Medical Genetics, Univ. Lille, CHU, Lille, France functions as a transcription factor, belonging to a basic helix
3
Dana-Farber Cancer Institute, Harvard Medical School, loop helix leucine zipper (bHLH-LZ) family [12]. The
Boston, MA, USA bHLH motif is characterized by two α-helices of about 50
4
Department of Hematology, Univ. Lille,, CHU, Lille, France amino acids connected by a loop of variable length, whereas
K. K. Jovanović et al.
Table 1 References need to be changed MYC deregulation in MM reported that plasmablasts display a distinctly lower level of
MGUS MM Ref BLIMP1 expression than PCs [27]. Of note, long-lived PCs
silence the cell cycle program, including the expression of
MYC translocations 3% 20–50% [35–37]
MYC, which is a target of BLIMP1-mediated repression
Gain of MYC <5% 15–20% [39, 40] [28].
MAPK mutations 7% 40% [34, 42, 43] Initial interaction of B cells with antigens and T cells
DIS3 mutations – 10% [49, 50] leads to transient upregulation of MYC during the early
MYC activation signature 0% 67% [33, 34] phases of GC formation [29, 30]. Inhibition of MYC
expression results in a complete absence of GCs, which
points out to the importance of this event for GC formation.
LZ dimerization motif is characterized by heptad repeats of In subsequent steps, upregulation of BCL6 takes place,
leucines. Transcription factors belonging to this family are which leads to repression of MYC, because BCL6 binds to
involved in regulation of neurogenesis, myogenesis, cell its promoter. This event is associated with the formation of
proliferation and differentiation, cell lineage determination, the DZ and expansion of highly proliferating B cells. MYC
sex determination, and other essential processes in eukar- is then re-expressed in a subset of activated cells of the LZ
yotic organisms [13]. MYC integrates signals from various that have increased nuclear factor-kB and Interferon reg-
pathways to direct gene expression programs and to reg- ulatory factor 4 (IRF4), but decreased BCL6 expression. LZ
ulate many biological functions, including ones influencing MYC-positive cells correspond to a sub-population of B
cell growth and proliferation–replication [14, 15], tran- cells with high-affinity BCRs that are prepared to reenter the
scription [16] and translation [17, 18], cellular metabolism DZ for a next round of proliferation and further acquisition
[19], and apoptosis [20]. As MYC regulates a large variety of Ig somatic mutations, whereas MYC-negative cells in the
of cell functions, it represents an attractive target for cancer LZ are considered to be sub-population of B cells ready to
therapy. exit the GC as memory cells or early plasmablasts [31],
The comprehension of mechanisms leading to MYC further differentiating to PCs.
deregulation and its function in tumors is critical to develop
new strategies to targeting MYC. In this review, we
describe the deregulations responsible for MYC activation Deregulation of MYC in MM
in MM, the functions of MYC in tumor progression, and the
strategies to targeting MYC in MM. MYC is a key regulator of MM
67% of MM, confirming that MYC activation is one of the was associated with a shorter survival in univariate analysis
central events leading to disease progression [33, 34]. [39, 40]. copy number alterations (CNA) data generated from
These works validate the central role of MYC activation whole-exome sequencing revealed gains of MYC in 19% of
development and progression of MM. Moreover, clinical the patients at the time of diagnosis. Among them, 38% had a
and biological data have informed about frequent MYC gain of MYC in the context of a MYC translocation and 62%
locus rearrangements and gains, MYC mRNA over- had focal or chromosomal gains alone [36]. Of note, gain of
expression, MYC protein stabilization, and deregulation of MYC is rarely seen in MGUS samples, suggesting its role in
pathways involving MYC (Table 1 and Fig. 1). tumor progression [41] (Table 1).
MYC translocations have been reported in 20–50% of NRAS and KRAS are the two most frequently mutated genes
patients with newly diagnosed MM [35–37]. These trans- in MM. Rat Sarcoma (RAS) family mutations are present in
locations involve the immunoglobulin (IG) loci (IGH > IGL about 30% of newly diagnosed MM and found at much
> IGK) and some non-Ig partners such as FAM46C, lower rate in MGUS, suggesting their role in disease pro-
FOXO3, and BMP6. In all cases, MYC is under the control gression [42, 43].
of enhancers or super-enhancers at the partner loci, which RAS pathway activation increases MYC stabilization.
results in overexpression of the oncogene [35, 36, 38]. The mitogen-activated protein kinase (MAPK) phosphor-
Patients bearing MYC translocations have decreased ylates MYC at Ser62, extending the half-life of this onco-
progression-free survival (PFS) and overall survival (OS) protein by preventing its proteolytic degradation [44, 45].
[36]. Interestingly, kataegis, a pattern of localized hyper- Of note, gene expression analysis study has demonstrated
mutations associated with APOBEC deregulation, is often that almost all RAS mutated MM tumors express the MYC
found at the site of MYC breakpoints, suggesting its role in activation signature [34]. In most of the cases, no IGH-
generating MYC translocation in MM [36]. Of note, MYC MYC translocations were identified in these RAS mutated
translocations are rarely detected in patients with MGUS samples, suggesting that RAS mutations are directly
and SMM (3% and 4%, respectively) [37] (Table 1). involved in MYC activation [34].
Gains and amplifications of MYC at 8q24.21 locus are pre- MicroRNAs and specifically the let-7 family also regulate
sent in about 15% of newly diagnosed MM patients, which MYC expression. The LIN28B/Let-7/MYC axis has been
K. K. Jovanović et al.
MYC
MYC
MYC MYC
Fig. 2 Bottom lines of the figure need to be changed MYC functions processes—DNA replication [15], transcription of MYC target genes
in cancer. Alterations of MYC commonly found in human cancers [57], regulation of splicing factors [60–62], ribosome biogenesis [63,
(translocations, gains, and transcriptional activation of MYC gene) 64], and cell cycle [73–75], as well as modification of the immune
result in overexpression of MYC protein, which influences key cellular microenvironment [84]. Pre-RC pre-replicative complex
reported in several cancers, [46] including MM [47]. that knockdown of IRF4 by RNA interference results in fast
LIN28B is a RNA-binding protein that regulates the let-7 non-apoptotic cell death in all MM cell lines tested, which
miRNA family. In physiological context, let-7 miRNAs was independent of other genetic abnormalities present in
repress MYC expression by binding to its 5′-untranslated each line. Gene expression profiling together with genome-
region (UTR) and activating the RNA-induced silencing wide chromatin immunoprecipitation analysis of IRF4-
complex. Deregulation of LIN28B induces a repression of binding sites have established MYC as direct target gene of
let-7, therefore leading to an overexpression of MYC [47]. IRF4 [54]. IRF4 binds directly to the MYC promoter region
Moreover, DIS3 functions as RNA-binding protein and and increases MYC expression, and MYC also creates
DIS3 inactivation increases LIN28B expression, which in positive autoregulatory feedback loop by transactivating
turn decreases mature let-7 and results in overexpression of IRF4. Moreover, there is a positive correlation between
downstream let-7 targets, such as MYC and RAS [48]. Of IRF4 and MYC expression levels in primary samples of
note, somatic mutations in DIS3 are present in 10% of MM patients with MM [54]. Of note, IRF4 is one of the recur-
samples [49, 50]. DIS3 mutations are mainly located within rently mutated genes in MM [42].
the major ribonuclease domains of the protein, thus
impairing the enzymatic activity of DIS3 [49, 51].
MYC function in cancer
IRF4 dependency and MYC
MYC activates DNA replication
IRF4 belongs to the interferon regulatory factor (IRF)
family, which consists of a broadly expressed set of tran- MYC has a direct role in the control of DNA replication in
scription factors first described as downstream regulators of a non-transcriptional manner and causes genomic
interferon signaling. Expression of IRF4 is limited to the instability and DNA damage [15]. Affinity purification of
immune system, with its role as a critical mediator of MYC-containing protein complex revealed that MYC
lymphoid cells development [52, 53]. interacts with the pre-replicative complex proteins such as
RNA interference screening studies have revealed IRF4 MCM2, MCM7, ORC2, Cdc6, and Cdt1. MYC localizes
to be an essential gene in MM [54]. It has been established to early sites of DNA synthesis in mammalian cells and
Targeting MYC in multiple myeloma
modulates DNA replication origin activity. MYC nuclear ribonucleoprotein particle assembly genes
overexpression increases in the number of DNA synthesis hnRNPA1 and hnRNPA2, PTB and PRTM5. Several
foci in early S-phase, consistent with an increase in examples illustrate that MYC-induced deregulation of
the number of active replicons [15]. This MYC-induced splicing leads to oncogenesis and tumor progression.
DNA replication activation is associated with DNA The alternative splicing of pyruvate kinase (PKM) is
damage and checkpoint activation and may explain the regulated by these splicing factors, generating two possible
presence of genomic alterations, such as aneuploidy, splicing variants—PKM1, which favors oxidative phos-
polycentric chromosomes, and chromosome breaks, which phorylation (adult isoform) and PKM2, which promotes
are associated with MYC deregulation during tumorigen- aerobic glycolysis (embryonic/tumor isoform) [60, 61].
esis [15, 55] (Fig. 2). Although MYC activates DNA MYC upregulates transcription of PTB, hnRNPA1, and
replication, it should be noted that, in MM, MYC is not hnRNPA2, ensuring a high PKM2/PKM1 ratio, which is
associated with marked increased proliferation like in responsible for tumor progression.
other cancers [34]. During lymphomagenesis, MYC upregulates transcrip-
tion of the core small nuclear ribonucleoprotein particle
MYC and transcription, two opposing models assembly gene, PRMT5. This regulatory effect is critical for
effective pre-mRNA splicing, cell survival, and prolifera-
It is estimated that MYC binds 10–15% of the genome [56]. tion [62]. These findings indicate that MYC-overexpressing
At low expression, MYC binds to E-box sequences of cells are in general more sensitive to splicing inhibition
active promoters pre-marked by H3K4me3 and RNA (Fig. 2).
polymerase II (Pol II). However, when overexpressed,
MYC binds larger numbers of promoters and enhancers, MYC activates ribosome biogenesis and protein
characterized by the presence of histone marks H3K4me1, synthesis
H3K4me3, and H3K27ac with a high H3K4me1/H3K4me3
ratio and controls transcription mediated by all three RNA MYC induces transcription of ribosomal RNA (rRNA) by
polymerases (Pol I, II, and III) [57]. Traditionally, MYC is binding to E-box motifs in their promoters and recruiting
thought to act as a transcription activator when it hetero- transformation/transcription domain-associated protein.
dimerizes to MAX and a transcription repressors when it This leads to remodeling the chromatin structure to a more
binds to MXD family transcription factors. permissive state, which stimulates the transcription of
Despite intensive research, the definition of MYC target rRNAs by RNA polymerase I [63, 64].
genes is still unclear and two different regulatory models Experiments performed in Eµ-Myc/ + ;L24+/- and Eµ-
exist: global vs. selective. The first model is supported by Myc/ + ;L38+/- mice (overexpression of MYC together with
two publications in 2012, suggesting that MYC acts as a haploinsufficiency of the ribosomal proteins RPL24 or
general amplifier of transcription that is present at all active RPL38, respectively) have provided evidence that the
gene promoters and enhancers in the genome, a phenom- ability of MYC to augment protein synthesis is necessary
enon called chromatin invasion [58, 59]. Here, high for its oncogenic potential. In Eμ-Myc transgenic mice, loss
expression of MYC would not bind and regulate selected of one allele of RPL24 or RPL38 genes coding for riboso-
target genes but rather amplify the output of existing gene mal proteins leads to suppression of lymphoma initiation.
expression program. However, a publication in 2014 pro- These results implicate that targeting selected ribosomal
posed an alternative scenario where MYC directly regulates biogenesis components could potentially be used to inhibit
a set of genes, activating or repressing their transcription MYC-driven tumorigenesis.
[16]. Genome-wide chromatin immunoprecipitation and MYC-driven cancers are also dependent on translation
RNA expression profiles during B-cell lymphomagenesis initiation and activity. The eIF4E-binding protein 1
enabled the distinction between direct and indirect effects of (EIF4EBP1) interdicts translation initiation by binding to
MYC on RNA biogenesis [16]. These results led to con- the translation factor eIF4E, and preventing recruitment of
clusion that chromatin invasion by MYC and RNA ampli- the translation machinery to mRNA. In the Eμ-MYC tumor
fication are independent events, and that MYC shows direct model, MYC overexpression induces mechanistic target of
effect only in terms of upregulation and downregulation of rapamycin (mTOR)-dependent hyperphosphorylation of
discrete groups of genes (Fig. 2). EIF4EBP1, resulting in an abrogation of eIF4E-binding
activity, which is required for cancer cell survival [65, 66].
MYC regulates splicing factors This finding provides evidence of synthetic lethality in
MYC-driven cancers, by inhibiting key downstream mole-
MYC is responsible for direct modulation of the transcrip- cular pathways required for MYC-driven tumorigenesis
tion of spliceosome machinery components, such as small (Fig. 2).
K. K. Jovanović et al.
Cell cycle, metabolism, and apoptosis anti-apoptotic BCL-2 is a common mechanism for evading
MYC-driven apoptosis. In human tumors where MYC is
Cell cycle overexpressed due to gain or translocation, various rear-
rangements in the BCL-2 locus have also been reported [79,
In normal cells, inhibition of MYC activity results in 80]. Results of assessing survival impact of simultaneously
invariable G0/G1 and G1/S cell cycle arrest [67, 68]. MYC elevated expression levels of MYC and BCL-2 in animal
promotes transition into S-phase of the cell cycle through models have provided evidence that overexpression of pro-
various mechanisms [69–72]. Genes induced by MYC survival BCL-2 compensates high levels of MYC, which
encode most of the essential cell cycle regulators. These would normally exhibit apoptotic effects [81–83].
MYC target genes include Cdks, cyclins, and E2F tran-
scription factors. Moreover, MYC antagonizes the activity MYC and the immune microenvironment
of cyclin-dependent kinase inhibitor such as p21 and p27,
by blocking CDKN1A (coding for p21) transcription or by Tumors need to escape immune surveillance. Over-
inducing Skp2, a protein involved in p27 degradation [73]. expression of immune-suppressive molecules such as
MYC also induces CUL1, which is a component of a E3 programmed death-ligand 1 (PD-L1) represents a key
ubiquitin ligase complex, required for efficient ubiquitina- mechanism of immune evasion in cancer. MYC regulates
tion and degradation of p27 [74], subsequently leading to S- the expression of two immune checkpoints proteins on
phase entry [75] (Fig. 2). the tumor cell surface: the innate immune regulator cluster
of differentiation 47 (CD47) and the adaptive immune
Metabolism checkpoint PD-L1 [84], by directly binding to their
promoters. MYC inactivation in mouse models induces
In order to maintain high proliferation rate, cancer cells downregulation of CD47 and PD-L1 expression levels and
must exhibit profound metabolic changes. MYC regulates enhanced the antitumor immune response, which was revert
transcription of several genes that participate in glycolysis by rescuing CD47 or PD-L1 expression, in which
and in glutaminolysis, such as glucose membrane trans- case tumors continue to grow. Thus, MYC appears to
porters such as GLUT1 (SLC2A1) and glutamine transporter have a role in the modulation of immune regulatory mole-
ASCT2 (SLC1A5) [76, 77]. Besides inducing expression of cules, representing a potential therapeutic vulnerability
these genes, MYC also favors specific mRNA splice var- (Fig. 2).
iants, such as glycolysis-affecting PKM2 over PKM1 [61].
Upregulation of endogenous normal MYC expression is
inhibited when there is growth factor withdrawal or nutrient Targeting MYC
insufficiency present. However, when MYC expression is
deregulated by chromosomal translocation or gene ampli- MM represents a MYC-driven cancer, which is a potential
fication, these negative feedback loops become ineffective therapeutic target in MM treatment. Direct inhibition of
in controlling MYC expression, and a constitutive cellular transcription factors such as MYC remains a challenge in the
growth program independent of nutrient availability is area of ligand discovery. Several approaches have been
supported by oncogenic MYC activity. As cancer cells are developed to directly or indirectly target MYC in MM
unable to turn off MYC, they are addicted to nutrients such (Fig. 3), some of which are evaluated in clinical trials
as glucose and glutamine, and this metabolic addiction of (Table 2).
constitutive MYC-activated cancer cells could potentially
yield therapeutic vulnerabilities [19]. MYC-targeting siRNA
Atezolizumab
TGR-1202 Durvalumab
CX-5461
CMLD010509
MYC
translation MYC
MYC
Direct inhibition of Prevent MYC/MAX Mycro3 Effective in mouse models [80, 81]
MYC dimerization KJ-Pyr-9 Effective in mouse models [80, 81]
MYC mRNA DCR-MYC Phase I (NCT02110563) [77]
degradation
Indirect inhibition Inhibit MYC OTX015 Phase I (NCT01713582) [86]
of MYC transcription CPI-0610 Phase I (NCT02157636) [87, 88]
RO6870810 Phase I (NCT03068351) [110]
Lenalidomide FDA approved [111, 112]
Inhibit MYC CMLD010509 Effective in mouse models [103]
translation TGR-1202 Phase I/II (NCT02867618) [100]
Inhibit ribosomal CX-5461 Effective in mouse models [107]
biogenesis
Target adaptive Anti-PD-L1 agents Atezolizumab Phase I (NCT02784483, [108]
immune checkpoint NCT02220842)
Durvalumab Phase II (NCT02807454, [109]
NCT03000452, NCT03003520)
compound, called CMLD010509, was shown to inhibit evaluated in clinical trials. However, direct interaction with
translation of a specific set of oncoproteins in MM that MYC remains a challenge due to both its structure and
define the oncogenic translation program supporting MM function as a transcription factor. Targeting transcription
oncogenesis, including MYC, MDM2, CCND1, MCL-1, factors require molecules modulating protein–protein or
and MAF. Inhibition of the oncogenic translation program DNA–protein interactions and with permeability properties
resulted in induction of an apoptotic response in MM cells enabling to enter the nucleus. Moreover, the very broad
in vitro and prolonged survival in MM xenograft model as functions of MYC in human cells might impair essential
well as the MYC-driven Vk*MYC transgenic mouse activity of MYC, such as stem cell renewal. Therefore,
model. Rocaglate compounds thus represent a novel ther- dissecting MYC functions to interact with specific down-
apeutic approach to targeting MYC in MM [111]. stream regulations represent an attractive approach to target
One of the key MYC downstream effect is upregulation MYC-driven cancers. Large high-throughput screen
of ribosomal biogenesis resulting in increased translation enabled identification of synthetic lethality MYC-activating
rate, which is characteristic of neoplastic cells [112]. tumors, such as inhibitions of spliceosome machinery or
Transcription of rRNA by the RNA polymerase I is a lim- translation initiation components. These approaches are
iting step of ribosomal biogenesis [63]. The small-molecule expected to yield new therapeutic strategies in the near
CX-5461 binds to selectivity factor 1 (SL1) of the RNA pol future, allowing for precision medicine in MYC-driven
I pre-initiation complex, preventing the recruitment of RNA cancers.
pol I and other cofactors to the rDNA transcriptional start
site [113]. Selective inhibition of Pol I transcription by CX- Compliance with ethical standards
5461 leads to p53-dependent apoptosis in Eμ-MYC lym-
Conflict of interest The authors declare that they have no conflict of
phoma cells [114], and to p53-independent cell death in interest.
MM cells, through degradation of MYC protein and tran-
script [115]. Moreover, it was found that MM cells with
higher expression of MYC exhibit greater sensitivity to CX- References
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