Role of protein kinases CK1α and CK2 in multiple myeloma: regulation of pivotal survival and stress-managing pathways
Manni et al. Journal of Hematology & Oncology
Role of protein kinases CK1α and CK2 in multiple myeloma: regulation of pivotal survival and stress-managing pathways
Sabrina Manni 0 1
Marilena Carrino 0 1
Francesco Piazza 0 1
0 Department of Medicine, Hematology Section, University of Padova , Via Giustiniani 2, 35128 Padova , Italy
1 Venetian Institute of Molecular Medicine , Padova , Italy
Multiple myeloma (MM) is a malignant tumor of transformed plasma cells. MM pathogenesis is a multistep process. This cancer can occur de novo (rarely) or it can develop from monoclonal gammopathy of undetermined significance (most of the cases). MM can be asymptomatic (smoldering myeloma) or clinically active. Malignant plasma cells exploit intrinsic and extrinsic bone marrow microenvironment-derived growth signals. Upregulation of stress-coping pathways is also instrumental to maintain MM cell growth. The phylogenetically related Ser/Thr kinases CSNK1A1 (CK1α) and CSNK2 (CK2) have recently gained a growing importance in hematologic malignancies arising both from precursors and from mature blood cells. In multiple myeloma, CK1α or CK2 sustain oncogenic cascades, such as the PI3K/AKT, JAK/STAT, and NF-κB, as well as propel stress-related signaling that help in coping with different noxae. Data also suggest that these kinases modulate the delivery of growth factors and cytokines from the bone marrow stroma. The “non-oncogene addiction” phenotype generated by the increased activity of CK1α and CK2 in multiple myeloma contributes to malignant plasma cell proliferation and survival and represents an Achilles' heel for the activity of small ATP competitive CK1α or CK2 inhibitors.
Multiple myeloma; CK1; CK2; Bone marrow microenvironment; Survival signaling pathways; Non-oncogene addiction
Multiple myeloma (MM) is the second most frequent
hematologic malignancy, accounting for about 13% of all
blood cancers [
]. The bulk of the tumor is represented
by transformed plasma cells (PCs), which accumulate
firstly in the bone marrow (BM) in a
microenvironmental niche that supports their growth [
]. Along with the
disease progression, malignant PCs lose their
dependency from the BM and gain features of autonomous
growth with widespread dissemination of plasma cell
]. Clinically, MM is characterized by target
organ damage, with anemia, renal insufficiency and bone
resorption/loss with bone pain, hypercalcemia, and
pathological fractures. In addition, MM patients develop
immune-paralysis with hypogammaglobulinemia and
susceptibility to infections .
The molecular and genetic features of MM have lately
been described. MM are divided in cases bearing
chromosomal translocations affecting the IgH locus (30%); cases
with hyperdiploidy (trisomies) of odd chromosomes 3, 5,
7, 9, 11, 15, 17, and 19 (40–45%); cases with both the
alterations (15%); and cases with other abnormalities (10–15%)
]. The genomic analysis of MM cases has revealed a
complex genetic architecture that suggests a continuous
clonal evolution in a Darwinian process and few recurrent
mutations concentrated in clusters of genes, which
regulate, among others, the translation process, chromatin
modification and gene transcription, including the nuclear
factor kappa-light-chain-enhancer of activated B cells
(NF-κB) pathway .
Besides intrinsic alterations in MM PCs, an aberrant
BM microenvironment participates in MM
pathogenesis. The stromal niche surrounding malignant PCs is
able to deliver trophic signals represented by cytokines,
such as interleukin-6 (IL-6) and tumor necrosis
factorα (TNF-α), growth factors, such as insulin-like growth
factor-I (IGF-I) and related proteins, and soluble
glycoproteins, such as Wnt and Hedgehog. All these
signaling cascades inside MM cells shift the milieu towards
osteoclast propelling features and promote aberrant
]. Therefore, MM cells and bone
marrow stromal cells (BMSCs) depend on a number of
signaling cascades whose regulation is still largely
unknown. MM cells rely also on intracellular pathways
that have the ability to manage a different array of
stresses, including the proteotoxic, replicative, and
oxidative stress [
]. Thus, molecules acting as “stress
managers” may become essential for the optimal fitness
of malignant PCs. Examples are the transcription factor
IRF4, which is part of a rewired transcriptional program
in malignant PCs as compared to normal counterparts
, the kinase ATR [
], and the scavenger enzyme
Mutations as well as hyper-function of certain
fundamental proteins and cascades may cause tumor
promotion and progression. In this context, it is not doubtable
that native or newly generated protein kinases (PK) may
become pivotal players. As a proof of concept that PK
may be central in oncogenesis is the clear evidence of
the lethal consequences for many tumor types caused by
their inhibition. Some examples are the drugs imatinib,
gefitinib, ibrutinib, or fostamatinib, which target a
number of receptor/cytosolic tyrosine kinases and have
proven to be clinically effective therapeutic options for
solid tumors, chronic myeloid leukemia (CML) or
chronic lymphocytic leukemia (CLL), and non-Hodgkin
lymphomas. However, despite the fact that in several B
cell malignancies protein kinases represent valid
therapeutic targets, this proof of principle is lacking in MM.
In this regard, among protein kinases driving MM
cell survival, recently, the Ser/Thr kinases CK1α and
CK2 have been shown to play an important role as
regulators of signal transduction and stress response
]. We will herein review CK1α and CK2 function
in MM and discuss the potential of targeting their
kinase activity as a suitable therapeutic strategy for this
B cell-derived tumor.
Protein kinase CK1α: emerging roles in cancer
CK1α belongs to a family of highly conserved
monomeric Ser/Thr kinases composed by seven members
encoded by different genes (α, β, γ1, γ2, γ3, δ, and ε),
displaying the highest homology in their kinase domains
(50–90% identical) with similar substrate specificity.
CK1 members regulate membrane biology, molecular
transport, signal transduction, transcription, translation,
and DNA damage response [
]. In the last few
years, CK1α, encoded by the CSNK1A1 gene, has been
involved in cancer with a role that seems multifaceted.
CK1α inhibition, leading to stabilization of β-catenin,
acts as a tumor promoter in the absence of p53 in
intestinal epithelial cells, while its inactivation does not turn
into tumor formation as long as p53 is active [
Nevertheless, CK1α is a tumor promoter in acute
myeloid leukemia (AML), provided there is an intact p53
. CK1α has been shown to negatively regulate
Rasinduced autophagy in models of Ras-driven
transformation by controlling the phosphorylation of FOXO3A on
S318/321 and its subsequent nuclear extrusion [
Other reports have involved CK1α in tumors. CK1α is a
tumor supporter in diffuse large B cell lymphoma
(DLBCL) of activated B cell subtype, inducing the
activation of NF-κB through the regulation of the CBM1
complex (CARD11, BCL10, MALT1) [
]. Mutations of CK1α
have been detected in melanoma, clear cell renal cell
], colon cancer , esophageal
], adult T cell leukemia/lymphoma [
del(5q) myelodisplatic syndromes (MDS) [
and colleagues demonstrated a prominent role of CK1α in
del(5q) MDS. Our group and others have demonstrated
an oncogenic role of CK1α in MM [
Altogether, a growing body of data points to a potential
role for CK1α in carcinogenesis in different tumor types.
Protein kinase CK2: an indispensable molecule for cancer
Protein kinase CK2 is a Ser/Thr kinase that regulates
critical cellular processes. It is composed by a tetramer
of two catalytic (α or α’) and two regulatory subunits (β)
]. The substrate specificity is believed to rely on the β
subunit even though tetramer-independent functions of
the α and β moieties have been recognized. CK2 has
been involved in cell proliferation, apoptosis,
transcription and translation, adhesion and motility, and
]. CK2 has hundreds of substrates [
among which are pivotal oncogenic proteins, like AKT
], c-Myc , NF-κB [
], and signal
transducer and activator of transcription 3 (STAT3) .
Given its multilateral involvement in cell biology, it is
not surprising that high CK2 activity and expression
have been correlated to poor prognosis and resistance to
anti-cancer agents in different types of cancers,
including breast [
], lung [
], prostate [
], renal [
bladder carcinoma [
], melanoma [
], and hematological
]. CK2 acts as a typical “non-oncogene
addiction” molecule, since cancer cells strongly rely on it
even though it is generally not altered by typical
mutations leading to a gain of function phenotype [
However, recently, CK2β deletions were identified in
15% of cases of early relapsing DLBCL patients
compared to those of late relapsing .
The mechanisms by which CK2 sustains malignant
tumor growth are numerous. CK2 promotes cancer cell
survival by activating tumor-promoting oncogenes
(such as c-Myc [
] in lymphoma, Ras-ERK [
], AKT [
] in bladder, colon, and
blood cancers) or by inhibiting tumor suppressors (such
as PTEN) [
CK2 also strongly supports the activity of important
signaling cascades, such as the NF-κB, in breast cancer [
as well as in multiple myeloma, lymphoma [
], Wnt-β-catenin, [
], Hedgehog in pleural
], and STAT3-dependent signaling in
solid and in hematological tumors [
phosphorylates NF-κB RelA/p65 on Ser529, increasing p65
transcriptional activity downstream external stimuli [
CK2 positively modulates STATs by phosphorylating
Ser727 of STAT3 [
]. This kinase regulates β-catenin
] and Gli1 function . Besides its role as a
signaling regulator, CK2 is involved in cellular processes
of stress-coping/fitness augmentation. For instance, CK2
regulates the DNA damage response [
, and endoplasmic reticulum (ER) stress [
major role in cell survival is believed to rely on CK2
modulation of caspase activity [
CK1α and CK2 in multiple myeloma: regulation of signal
Others and our group demonstrated that CK1α is a
pro-growth kinase in MM. In the work by Hu et al.
], CK1α was found to promote survival and
proliferation of MM cell lines and cMyc/KRasV12-transduced
BaF3 cells in xenograft mouse models. CK1α inhibition
led to higher interferon-α and TNF-α signaling. More
recently, we demonstrated that CK1α is highly
expressed in the vast majority of MM patient PCs (in a
large microarray data set series) compared to that in
healthy PCs [
]. CK1α loss of function with a
panCK1 inhibitor (D4476) or RNA interference (RNAi) was
accompanied to MM cell apoptosis, cell cycle arrest
and downregulation of β-catenin, and AKT survival
signaling, in a mechanism that could involve caspase and
]. Of note, CK1α inactivation was able to
overcome BMSCs protection. Moreover, CK1α inhibition
synergically boosted bortezomib and lenalidomide
cytotoxicity. Interestingly, lenalidomide treatment of MM
cells determined a deregulation of CK1α expression, in
a time- and dose-dependent manner, in a mechanism
similar to that observed in other cell types [
CK2 is overexpressed and enzymatically more active in
malignant MM PCs from patients and cell lines compared
to that in healthy controls [
]. CK2 was found localized
in the cytoplasm, in the nucleus, and in a small fraction
also in the ER of malignant PCs [
]. The use of ATP
competitive CK2-specific inhibitors like tBB, K27, and the
newly developed clinically graded CX-4945 (silmitasertib)
caused malignant PCs apoptosis, being less toxic to the
non-malignant counterparts [
8, 15, 16, 71
]. From a
molecular standpoint, CK2 inactivation with chemicals or by
RNAi in MM impacted on two main signaling pathways,
the NF-κB and the JAK-STAT cascades, which are known
to exert fundamental roles in MM pathogenesis. CK2
blockade was associated to an accumulation of the
inhibitor of NF-κB (IκBα) at baseline conditions as well as upon
a strong NF-κB-activating stimulus, such as TNF-α.
Consequently, the transcriptional activity of NF-κB was found
substantially compromised. Moreover, CK2 inhibition led
to an impaired phosphorylation of STAT3 on Tyr705 and
Ser727. Growth stimuli, such as IGF-I and IL-6, were not
able to overcome the lower cell survival frequency
consequent to CK2 inhibition, suggesting a central role for this
protein kinase downstream manifold signaling pathways.
As a result, myeloma cells with less active CK2 were much
more sensitive to the cytotoxic effect of a
chemotherapeutic drug employed in MM, such as melphalan or the
newgeneration drug proteasome inhibitor bortezomib.
The role of CK1α and CK2 on MM survival signaling
events and on response to drugs is summarized in Fig. 1.
CK1α and CK2 in multiple myeloma: regulation of
homeostatic/stress response pathways
A mechanism accounting for CK2-driven regulation of
multiple signaling cascades is the one described by
]. CK2 phosphorylates the co-chaperone
Cdc37 on Ser13. This phosphorylation enables Cdc37 to
tighten its association with the chaperone Hsp90 and
with a number of client protein kinases, many of which
are important in the signal transduction across different
proliferative and survival pathways. Thus, CK2 exerts a
“mastermind-like” control on many cellular functions.
This role is believed to be exquisitely important in the
context of malignant transformation, where signaling
modules are overexploited by an increased proliferation/
survival/stress-coping need. In particular, in MM, the ER
stress induced unfolded protein response (UPR) aimed
at coping with unfolded protein load in the ER. UPR can
end up in a compensatory response or (if the ER stress
is prolonged/overwhelming) in apoptosis. Analyzing
whether CK2 could impact on the proteotoxic/unfolded
protein stress in MM, we found that a fraction of CK2 is
localized in the ER and when ER stress was elicited by
thapsigargin, the CK2 kinase activity raised . Upon
CK2 inactivation, we observed a number of changes in
the homeostatic molecules regulating the ER stress/UPR:
a decreased expression of the co-chaperone Bip/Grp78
and of the kinase/endoribonuclease IRE1α (which was
also less phosphorylated), but an activation of the kinase
PERK (which was instead more phosphorylated at
Thr981) and of the downstream eukaryotic initiation
factor 2-eIF2α (more phosphorylated on Ser51).
Consequently, the UPR output was of a reduced synthesis of
Bip/Grp78 messenger RNA (mRNA) while there was an
increased expression of ATF6-dependent EDEM mRNA,
suggesting a negative role of CK2 on the ATF6 branch
of the UPR (Fig. 2). More importantly from a therapeutic
standpoint was the observation that the combined
inactivation of CK2 (with a chemical inhibitor) and of
Hsp90 (with 17-AAG) caused a synergistic cytotoxic
effect on MM cells both in vitro and in vivo in mouse
xenograft models. These data in MM reconcile with
others’ data in different tumor cells demonstrating that
CK2 maintains the ER stress response homeostasis [
Furthermore, CK2 seems critical for the ubiquitin
proteasome clearance of proteins in MM and mantle cell
lymphoma (MCL) [
]. When inhibited together with
the proteasome, CK2 was found instrumental for MM
and MCL cell survival as well as for the regulation of
poly-ubiquitylated proteins. Bortezomib and CK2
inhibitors synergized in inducing MM cell death.
It has been demonstrated in some cancer cells that
also CK1, together with CK2 and GSK3β, takes part in
the regulation of Hsp70 and Hsp90, influencing their
binding to the co-chaperones HOP (Hsp70-Hsp90
organizing protein) and the chaperone-binding ubiquitin
ligase CHIP to determine the cellular protein folding/
degradation balance [
]. The C-terminal
phosphorylation of Hsp70 and Hsp90 in proliferating cancer cells
enhances the assembly with HOP, increasing its protein
folding activity. The non-phosphorylated chaperones
preferentially bind to CHIP, mediating degradation of
client proteins. It has been shown that melanoma,
bladder, gastric, lung, breast, and pancreas cancer cells
contain high levels of HOP, leading to high proliferation.
Moreover, primary human breast tissue showed
increased phosphorylated chaperones, compared to
healthy samples. Even if a clear function of CK2 in UPR
has been demonstrated in MM, given the role of CK1 on
HOP and CHIP co-chaperones in other cancers, it is
likely that also CK1α takes part in ER/stress, UPR in
MM. Therefore, further research will have to clarify the
exact role of CK1α in Hsp90-Hsp70 co-chaperone
assembly and regulation in MM.
In the paper by Fernandez-Saiz et al. [
], a novel role
for CK2 was discovered in relation to nutrients and
growth factor withdrawal. The proteins telomere
maintenance 2 (Tel2) and Tel2 interacting protein 1 (Tti1)
were shown to be critical for the stability of PI3K-related
kinase complex mammalian target of rapamycin
complex 1 (mTORC1) by influencing assembly and
maturation and were discovered to be targets of the
E3ubiquitin ligase SCFFbxo9. In the absence of trophic
signals, SCFFbxo9 targets Tel2 and Tti1, thereby
destabilizing mTORC1 complex. As a result, the feedback
inhibition on the mTORC2 complex is relieved and the
activity of the mTORC2 complex is sustained, allowing
the cell to maintain the survival state. This
SCFFbxo9dependent ubiquitination was found to be triggered by a
CK2-executed priming phosphorylation of Ser485 on
Tel2 and of Ser828 on Tti1 (Fig. 3). In roughly 30% of
MM, SCFFbxo9 was found overexpressed whereas Tel2
and Tti1 downexpressed. In these MM cases, AKT was
overactive. Thus, CK2 might be a central regulator of
AKT activity in a subset of MM.
CK2 and CK1α role in bone marrow MM-stroma-delivered
Our group has demonstrated that CK2 is contributory in
supporting pivotal features of the BM microenvironment in
]. The protective anti-apoptotic signals delivered by
BMSCs are neutralized by CK2 inactivation. From a cellular
and molecular standpoint, we observed that CK2 maintains
a pro-survival signaling program from BMSCs to MM cells.
Intriguingly, the inhibition of CK2 in BMSCs was
accompanied by apoptosis of co-cultured MM cells, indicating the
essentiality of the kinase in promoting growth signals from
BMSCs towards MM cells. CK2 silencing in BMSCs caused
a time-dependent inactivation of NF-κB and STAT3 in
BMSCs and in MM cells. Indeed, the expression of IL-6
and TNF-α cytokines, mostly dependent on the activity of
NF-κB and STAT3, was markedly reduced upon CK2
knockdown. An unforeseen result was the downregulation
of the chemokine receptor CXCR4 in MM cells upon CK2
inhibition and consequently of the migratory potential of
MM cells towards a concentration gradient of the
respective ligand CXCL12 or SDF1α. The axis CXCL12/CXCR4
has been demonstrated to play an important role in MM
cell homing in the protective BM niche, and inhibitors of
CXCR4 are currently under scrutiny in clinical trials.
Moreover, in this study, we provided evidence supporting a role
for CK2 in bone homeostasis, which could be relevant in
MM-associated bone disease. CK2 inhibition caused a
relatively small cytotoxicity against human osteoblast cell line
whereas it led to a dramatic reduction of human
BMderived osteoclast generation. Moreover, the
osteoclastdependent MM cell survival was reduced upon CK2
inhibition. The role of CK2 on MM-stroma-delivered
signals is summarized in Fig. 4.
Regarding CK1α, this kinase provided a growth
advantage in MM plasma cellular clone evolution by impinging
on pivotal signalling cascades important for MM cell
survival. In particular, by inhibiting PCs and bone BM survival
signaling molecules (like β-catenin and AKT), CK1α
silencing/inhibition determined MM cell apoptosis, even when
co-cultured with BMSCs, overcoming stromal cell
]. Moreover CK1α inhibition enhanced bortezomib
and lenalidomide cytotoxicity on MM cells grown alone
and/or on stromal cells, pointing to a function of CK1α on
chemotherapy resistance. A recent study by Costa et al.
] reported a role of CK1α in human dendritic cell (DC)
maturation, modulating the mesenchymal stromal cell
(MSC) inhibitory properties on DC evolution. CK1α
silencing in MSC blunted the inhibitory effect of MSC on DC
differentiation, increasing the expression of DC maturation
markers (CD80, DC86, CD209) in a mechanism similar to
that exerted by lenalidomide on DC of MM patients. This
could suggest a potential role of CK1α in the modulation
of MSC immunomodulatory properties. Further
experiments would be necessary to prove this concept.
CK1α and CK2 inhibition as a rational therapeutic approach
Protein kinases are rational therapeutic targets since
they are druggable with small molecule inhibitors. The
proof-of-concept of the effectiveness of anti-kinase
therapy was first shown in chronic myeloid leukemia, in
which the inhibitor imatinib mesylate has successfully
targeted the aberrant kinase activity of BCR-ABL1 [
Thereafter, a number of kinase inhibitors have entered
the clinical arena. Recently, the B cell receptor signaling
inhibitors idelalisib (which targets the PI3Kδ) and
ibrutinib (which targets BTK) have shown an unprecedented
clinical activity in B cell neoplasms [
Nevertheless, in the anti-MM therapeutic armamentarium, kinase
inhibitors are still lacking on the clinical ground.
The protein kinases CK1α and CK2 here discussed
have demonstrated to play an important pro-survival
role in MM. Thus, their inhibition could represent a
rational approach in the therapy of this B cell malignancy.
Recently, our group has shown that protein kinase CK2
sustains the growth of many blood cancers, including
], MCL [
], DLBCL [
], and AML [
Moreover, the CK2 inhibitor CX-4945 is now in phase I
clinical trial in solid tumors and relapsed/refractory
MM. Clinical-grade, oral ATP-competitive small
molecule CK2 inhibitors have been described and tested in
preliminary clinical trials in solid tumors and also MM,
even though no results of these trials have been
published. These already available drugs or other
compounds in development could be tested in combination
therapies with conventional or novel agents. Indeed,
CK2 inhibitors boost chemotherapy toxicity in cultured
] and other hematologic [
] and solid
tumor cells [
]. However, CK2 inhibition has proven to
be a rational strategy also in combination with novel
agents under study or already available in the therapy of
MM. In particular, CK2 inhibition combined with the
Hsp90 inhibitors geldanamycin or 17-AAG showed a
remarkable in vitro and in vivo synergistic/cooperative
cytotoxic activity in mouse models of MM [
Moreover, the association of the proteasome inhibitor
bortezomib with K27 or CX-4945 showed a synergistic
cytotoxic effect on MM and MCL cells [
Since CK2 inhibition is associated with the impairment
of NF-κB and STAT3 activation and signaling, a rational
use of CK2 inhibitors would be together with NF-κB and
STAT3 inhibitors. In support of this approach, data from
our laboratory have demonstrated that CK2 inhibitors
and STAT3 or IKK inhibitors may cooperate in inducing
cell killing of AML blasts [
]. If this holds true also in
MM, which is a malignancy highly dependent on these
two cascades, remains to be determined.
On the contrary, CK1α inhibition remains still an
approach far from applicability in the clinical scenario,
since no selective inhibitors targeting only this isoform
of the CK1 family are available (D4476 is believed to be
a dual CK1α/δ inhibitor). Nevertheless, the data here
discussed support the idea that targeting CK1α might be
beneficial at least in a subset of high-expressing MM
patients. Moreover, it could always be possible to envision
the dual CK1α/δ inhibition as an alternative approach,
even if more data should be produced in this regard.
Altogether, our in vitro studies indicate that CK1α
inactivation may boost bortezomib and lenalidomide
cytotoxicity. Further research should be pursued to confirm
and extend these data.
In conclusion, CK1a and CK2 are two Ser/Thr kinases
whose role in controlling signaling pathways involved in
proliferation, survival and stress resistance in MM has
been robustly established. Moreover, the results highlight
the role of CK1α and CK2 in sustaining
BMSCsdelivered growth clues to MM cells suggesting that these
kinases could represent targets to disrupt MM cell
intrinsic as well as extrinsic survival mechanisms. Even
though most of the data on the role of CK1α and CK2
in MM have been generated in preclinical experimental
models, the strategy of inhibition of these two kinases
appears to lay on a strong rationale. It could be
anticipated that the inhibition of CK1α and/or CK2 could
cooperate or synergize with conventional or novel
antiMM agents. CK1α and CK2 might therefore be taken
into consideration for future therapeutic strategies in the
treatment of this hard-to-defeat malignancy.
AML: Acute myeloid leukemia; ATR: Ataxia telangiectasia and Rad3-related
protein; BM: Bone marrow; BMSCs: Bone marrow stromal cells; BTK: Bruton
tyrosine kinase; CLL: Chronic lymphocytic leukemia; CML: Chronic myeloid
]naphthyridine-8carboxylic acid); D4476:
]dioxin-6-yl)-5-pyridin-2yl-1H-imidazol-2-yl]benzamide); DLBCL: Diffuse large B cell lymphoma;
EDEM: ER-degradation-enhancing-α-mannidose-like protein; ER: Endoplasmic
reticulum; ERK: Extracellular signal-regulated kinase; FGF-3: Fibroblast growth
factor 3; GSK3: Glycogen synthase kinase 3; HOP: Hsp70-Hsp90 organizing
protein; IGF-I: Insulin-like growth factor-I; IL-6: Interleukin-6; IRF4: Interferon
regulatory factor 4; MCL: Mantle cell lymphoma; MDS: Myelodisplatic
syndromes; MM: Multiple myeloma; MSC: Mesenchymal stromal cells;
mTORC1: Mammalian target of rapamycin complex 1; NF-κB: Nuclear factor
kappa-light-chain-enhancer of activated B cells; PCs: Plasma cells;
PI3K: Phosphoinositide 3-kinase; PTEN: Phosphatase and tensin homolog;
RNAi: RNA interference; STAT3: Signal transducer and activator of
transcription 3; Tel2: Telomere maintenance 2; TNF-α: Tumor necrosis
factorα; Tt1: Tel2 interacting protein 1; UPR: Unfolded protein response
This work was supported by a grant from the Associazione Italiana per la
Ricerca sul Cancro (AIRC) to FP (IG 14481 and IG 18387). SM was supported
by a Fondazione Umberto Veronesi fellowship.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated
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All authors have contributed to revising the manuscript. All authors have
read and approved the final manuscript.
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
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1. Palumbo A , Anderson K. Multiple myeloma . N Engl J Med . 2011 ; 364 : 1046 - 60 .
2. Podar K , Chauhan D , Anderson KC . Bone marrow microenvironment and the identification of new targets for myeloma therapy . Leukemia . 2009 ; 23 : 10 - 24 .
3. Manier S , Sacco A , Leleu X , Ghobrial IM , Roccaro AM . Bone marrow microenvironment in multiple myeloma progression . J Biomed Biotechnol . 2012 ; 2012 : 157496 .
4. Bahlis NP , NJ. Targeting of adhesion molecules as a therapeutic strategy in multiple myeloma . Curr Cancer Drug Targets . 2012 ; 12 : 776 - 96 .
5. Hussein MA . Multiple myeloma: most common end-organ damage and management . J Natl Compr Canc Netw . 2007 ; 5 : 170 - 8 .
6. Kuehl WM , Bergsagel PL . Molecular pathogenesis of multiple myeloma and its premalignant precursor . J Clin Invest . 2012 ; 122 : 3456 - 63 .
7. Corre J , Munshi N , Avet-Loiseau H . Genetics of multiple myeloma: another heterogeneity level? Blood . 2015 ; 125 : 1870 - 6 .
8. Manni S , Toscani D , Mandato E , Brancalion A , Quotti Tubi L , Macaccaro P , et al. Bone marrow stromal cell-fueled multiple myeloma growth and osteoclastogenesis are sustained by protein kinase CK2 . Leukemia . 2014 ; 28 : 2094 - 7 .
9. Mitsiades CS , Mitsiades NS , McMullan CJ , Poulaki V , Kung AL , Davies FE , et al. Antimyeloma activity of heat shock protein-90 inhibition . Blood. 2006 ; 107 : 1092 - 100 .
10. Cea M , Cagnetta A , Adamia S , Acharya C , Tai Y-T , Fulciniti M , et al. Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells . Blood . 2016 ; 127 : 1138 - 50 .
11. Ocio EM , San Miguel JF. The DAC system and associations with multiple myeloma . Investig New Drugs . 2010 ; 28 ( Suppl 1 ): S28 - 35 .
12. Shaffer AL , Emre NCT , Lamy L , Ngo VN , Wright G , Xiao W , et al. IRF4 addiction in multiple myeloma . Nature . 2008 ; 454 : 226 - 31 .
13. Cottini F , Hideshima T , Suzuki R , Tai Y-T , Bianchini G , Richardson PG , et al. Synthetic lethal approaches exploiting DNA damage in aggressive myeloma . Cancer Discov . 2015 ; 5 : 972 - 87 .
14. Hurt EM , Thomas SB , Peng B , Farrar WL . Integrated molecular profiling of SOD2 expression in multiple myeloma . Blood . 2007 ; 109 : 3953 - 62 .
15. Manni S , Brancalion A , Tubi LQ , Colpo A , Pavan L , Cabrelle A , et al. Protein kinase CK2 protects multiple myeloma cells from ER stress-induced apoptosis and from the cytotoxic effect of HSP90 inhibition through regulation of the unfolded protein response . Clin Cancer Res . 2012 ; 18 : 1888 - 900 .
16. Manni S , Brancalion A , Mandato E , Quotti Tubi L , Tubi LQ , Colpo A , et al. Protein kinase CK2 inhibition down modulates the NF-kappaB and STAT3 survival pathways, enhances the cellular proteotoxic stress and synergistically boosts the cytotoxic effect of bortezomib on multiple myeloma and mantle cell lymphoma cells . PLoS One . 2013 ; 8 : e75280 .
17. Manni S , Carrino M , Manzoni M , Gianesin K , Nunes SC , Costacurta M , et al. Inactivation of CK1alpha in multiple myeloma empowers drug cytotoxicity by affecting AKT and beta-catenin survival signaling pathways . Oncotarget . 2017 ; 8 : 14604 - 19 .
18. Knippschild U , Gocht A , Wolff S , Huber N , Lohler J , Stoter M. The casein kinase 1 family: participation in multiple cellular processes in eukaryotes . Cell Signal . 2005 ; 17 : 675 - 89 .
19. Knippschild U , Kruger M , Richter J , Xu P , Garcia-Reyes B , Peifer C , et al. The CK1 family: contribution to cellular stress response and its role in carcinogenesis . Front Oncol . 2014 ; 4 : 96 .
20. Elyada E , Pribluda A , Goldstein RE , Morgenstern Y , Brachya G , Cojocaru G , et al. CKIalpha ablation highlights a critical role for p53 in invasiveness control . Nature . 2011 ; 470 : 409 - 13 .
21. Pribluda A , Elyada E , Wiener Z , Hamza H , Goldstein RE , Biton M , et al. A senescence-inflammatory switch from cancer-inhibitory to cancerpromoting mechanism . Cancer Cell . 2013 ; 24 : 242 - 56 .
22. Jaras M , Miller PG , Chu LP , Puram RV , Fink EC , Schneider RK , et al. Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia . J Exp Med . 2014 ; 211 : 605 - 12 .
23. Cheong JK , Zhang F , Chua PJ , Bay BH , Thorburn A , Virshup DM . Casein kinase 1alpha-dependent feedback loop controls autophagy in RAS-driven cancers . J Clin Invest . 2015 ; 125 : 1401 - 18 .
24. Bidere N , Ngo VN , Lee J , Collins C , Zheng L , Wan F , et al. Casein kinase 1alpha governs antigen-receptor-induced NF-kappaB activation and human lymphoma cell survival . Nature . 2009 ; 458 : 92 - 6 .
25. Schittek B , Sinnberg T. Biological functions of casein kinase 1 isoforms and putative roles in tumorigenesis . Mol Cancer . 2014 ; 13 : 231 .
26. Sato Y , Yoshizato T , Shiraishi Y , Maekawa S , Okuno Y , Kamura T , et al. Integrated molecular analysis of clear-cell renal cell carcinoma . Nat Genet . 2013 ; 45 : 860 - 7 .
27. Okerberg ES , Hainley A , Brown H , Aban A , Alemayehu S , Shih A , et al. Identification of a tumor specific, active-site mutation in casein kinase 1alpha by chemical proteomics . PLoS One . 2016 ; 11 : e0152934 .
28. Dulak AM , Stojanov P , Peng S , Lawrence MS , Fox C , Stewart C , et al. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity . Nat Genet . 2013 ; 45 : 478 - 86 .
29. Kataoka K , Nagata Y , Kitanaka A , Shiraishi Y , Shimamura T , Yasunaga J-I , et al. Integrated molecular analysis of adult T cell leukemia/lymphoma . Nat Genet . 2015 ; 47 : 1304 - 15 .
30. Schneider RK , Adema V , Heckl D , Jaras M , Mallo M , Lord AM , et al. Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS . Cancer Cell . 2014 ; 26 : 509 - 20 .
31. Hu Y , Song W , Cirstea D , Lu D , Munshi NC , Anderson KC . CSNK1alpha1 mediates malignant plasma cell survival . Leukemia . 2015 ; 29 : 474 - 82 .
32. Litchfield DW . Protein kinase CK2: structure, regulation and role in cellular decisions of life and death . Biochem J . 2003 ; 369 : 1 - 15 .
33. Gowda C , Song C , Kapadia M , Payne JL , Hu T , Ding Y , et al. Regulation of cellular proliferation in acute lymphoblastic leukemia by Casein Kinase II (CK2) and Ikaros . Adv Biol Regul . 2017 ; 63 : 71 - 80 .
34. Piazza F , Manni S , Ruzzene M , Pinna LA , Gurrieri C , Semenzato G. Protein kinase CK2 in hematologic malignancies: reliance on a pivotal cell survival regulator by oncogenic signaling pathways . Leukemia . 2012 ; 26 : 1174 - 9 .
35. Piazza F , Manni S , Semenzato G . Novel players in multiple myeloma pathogenesis: role of protein kinases CK2 and GSK3 . Leuk Res . 2013 ; 37 : 221 - 7 .
36. Meggio F , Pinna LA . One-thousand-and-one substrates of protein kinase CK2? FASEB J. 2003 ; 17 : 349 - 68 .
37. Di Maira G , Salvi M , Arrigoni G , Marin O , Sarno S , Brustolon F , et al. Protein kinase CK2 phosphorylates and upregulates Akt/PKB . Cell Death Differ. 2005 ; 12 : 668 - 77 .
38. Guerra B . Protein kinase CK2 subunits are positive regulators of AKT kinase . Int J Oncol . 2006 ; 28 : 685 - 93 .
39. Channavajhala P , Seldin DC . Functional interaction of protein kinase CK2 and c-Myc in lymphomagenesis . Oncogene . 2002 ; 21 : 5280 - 8 .
40. Romieu-Mourez R , Landesman-Bollag E , Seldin DC , Sonenshein GE . Protein kinase CK2 promotes aberrant activation of nuclear factor-kappaB, transformed phenotype, and survival of breast cancer cells . Cancer Res . 2002 ; 62 : 6770 - 8 .
41. Landesman-Bollag E , Romieu-Mourez R , Song DH , Sonenshein GE , Cardiff RD , Seldin DC . Protein kinase CK2 in mammary gland tumorigenesis . Oncogene . 2001 ; 20 : 3247 - 57 .
42. O-charoenrat P , Rusch V , Talbot SG , Sarkaria I , Viale A , Socci N , et al. Casein kinase II alpha subunit and C1-inhibitor are independent predictors of outcome in patients with squamous cell carcinoma of the lung . Clin Cancer Res . 2004 ; 10 : 5792 - 803 .
43. Laramas M , Pasquier D , Filhol O , Ringeisen F , Descotes J-L , Cochet C. Nuclear localization of protein kinase CK2 catalytic subunit (CK2alpha) is associated with poor prognostic factors in human prostate cancer . Eur J Cancer . 2007 ; 43 : 928 - 34 .
44. Stalter G , Siemer S , Becht E , Ziegler M , Remberger K , Issinger OG . Asymmetric expression of protein kinase CK2 subunits in human kidney tumors . Biochem Biophys Res Commun . 1994 ; 202 : 141 - 7 .
45. Zhang X , Yang X , Yang C , Li P , Yuan W , Deng X , et al. Targeting protein kinase CK2 suppresses bladder cancer cell survival via the glucose metabolic pathway . Oncotarget . 2016 ; 7 : 87361 - 72 .
46. Zhou B , Ritt DA , Morrison DK , Der CJ , Cox AD . Protein kinase CK2alpha maintains extracellular signal-regulated kinase (ERK) activity in a CK2alpha kinase-independent manner to promote resistance to inhibitors of RAF and MEK but not ERK in BRAF mutant melanoma . J Biol Chem . 2016 ; 291 : 17804 - 15 .
47. Mandato E , Manni S , Zaffino F , Semenzato G , Piazza F. Targeting CK2 -driven non-oncogene addiction in B-cell tumors . Oncogene . 2016 ; 35 : 6045 - 52 .
48. Ruzzene M , Pinna LA . Addiction to protein kinase CK2: a common denominator of diverse cancer cells? Biochim Biophys Acta . 1804 ; 2010 : 499 - 504 .
49. Broseus J , Chen G , Hergalant S , Ramstein G , Mounier N , Gueant J-L , et al. Relapsed diffuse large B-cell lymphoma present different genomic profiles between early and late relapses . Oncotarget . 2016 ; 7 : 83987 - 4002 .
50. Whitmarsh AJ . Casein kinase 2 sends extracellular signal-regulated kinase nuclear . Mol Cell Biol . 2011 ; 31 : 3512 - 4 .
51. Ponce DP , Yefi R , Cabello P , Maturana JL , Niechi I , Silva E , et al. CK2 functionally interacts with AKT/PKB to promote the beta-catenin-dependent expression of survivin and enhance cell survival . Mol Cell Biochem . 2011 ; 356 : 127 - 32 .
52. Park JH , Kim JJ , Bae Y-S. Involvement of PI3K-AKT-mTOR pathway in protein kinase CKII inhibition-mediated senescence in human colon cancer cells . Biochem Biophys Res Commun . 2013 ; 433 : 420 - 5 .
53. Ruzzene M , Bertacchini J , Toker A , Marmiroli S . Cross-talk between the CK2 and AKT signaling pathways in cancer . Adv Biol Regul . 2017 ; 64 : 1 - 8 .
54. Quotti Tubi L , Canovas Nunes S , Brancalion A , Doriguzzi Breatta E , Manni S , Mandato E , et al. Protein kinase CK2 regulates AKT, NF-kappaB and STAT3 activation, stem cell viability and proliferation in acute myeloid leukemia . Leukemia . 2017 ; 31 : 292 - 300 .
55. Silva A , Jotta PY , Silveira AB , Ribeiro D , Brandalise SR , Yunes JA , et al. Regulation of PTEN by CK2 and Notch1 in primary T-cell acute lymphoblastic leukemia: rationale for combined use of CK2- and gammasecretase inhibitors . Haematologica . 2010 ; 95 : 674 - 8 .
56. Romieu-Mourez R , Landesman-Bollag E , Seldin DC , Traish AM , Mercurio F , Sonenshein GE . Roles of IKK kinases and protein kinase CK2 in activation of nuclear factor-kappaB in breast cancer . Cancer Res . 2001 ; 61 : 3810 - 8 .
57. Ponce DP , Maturana JL , Cabello P , Yefi R , Niechi I , Silva E , et al. Phosphorylation of AKT/PKB by CK2 is necessary for the AKT-dependent upregulation of beta-catenin transcriptional activity . J Cell Physiol . 2011 ; 226 : 1953 - 9 .
58. Zhang S , Yang Y-L , Wang Y , You B , Dai Y , Chan G , et al. CK2alpha, overexpressed in human malignant pleural mesothelioma, regulates the Hedgehog signaling pathway in mesothelioma cells . J Exp Clin Cancer Res . 2014 ; 33 : 93 .
59. Wang D , Westerheide SD , Hanson JL , Baldwin AS Jr. Tumor necrosis factor alpha-induced phosphorylation of RelA/p65 on Ser529 is controlled by casein kinase II . J Biol Chem . 2000 ; 275 : 32592 - 7 .
60. Seldin DC , Landesman-Bollag E , Farago M , Currier N , Lou D , Dominguez I. CK2 as a positive regulator of Wnt signalling and tumourigenesis . Mol Cell Biochem . 2005 ; 274 : 63 - 7 .
61. Gao Y , Wang HY . Casein kinase 2 is activated and essential for Wnt/betacatenin signaling . J Biol Chem . 2006 ; 281 : 18394 - 400 .
62. Zhang S , Wang Y , Mao J-H , Hsieh D , Kim I-J , Hu L-M , et al. Inhibition of CK2alpha down-regulates Hedgehog/Gli signaling leading to a reduction of a stem-like side population in human lung cancer cells . PLoS One . 2012 ; 7 : e38996 .
63. Siddiqui-Jain A , Bliesath J , Macalino D , Omori M , Huser N , Streiner N , et al. CK2 inhibitor CX-4945 suppresses DNA repair response triggered by DNAtargeted anticancer drugs and augments efficacy: mechanistic rationale for drug combination therapy . Mol Cancer Ther . 2012 ; 11 : 994 - 1005 .
64. Olsen BB , Wang S-Y , Svenstrup TH , BPC C , Guerra B . Protein kinase CK2 localizes to sites of DNA double-strand break regulating the cellular response to DNA damage . BMC Mol Biol . 2012 ; 13 : 7 .
65. Olsen BB , Svenstrup TH , Guerra B . Downregulation of protein kinase CK2 induces autophagic cell death through modulation of the mTOR and MAPK signaling pathways in human glioblastoma cells . Int J Oncol . 2012 ; 41 : 1967 - 76 .
66. Buontempo F , Orsini E , Lonetti A , Cappellini A , Chiarini F , Evangelisti C , et al. Synergistic cytotoxic effects of bortezomib and CK2 inhibitor CX-4945 in acute lymphoblastic leukemia: turning off the prosurvival ER chaperone BIP/ Grp78 and turning on the pro-apoptotic NF-kappaB . Oncotarget . 2016 ; 7 : 1323 - 40 .
67. Turowec JP , Duncan JS , Gloor GB , Litchfield DW . Regulation of caspase pathways by protein kinase CK2: identification of proteins with overlapping CK2 and caspase consensus motifs . Mol Cell Biochem . 2011 ; 356 : 159 - 67 .
68. Turowec JP , Vilk G , Gabriel M , Litchfield DW . Characterizing the convergence of protein kinase CK2 and caspase-3 reveals isoform-specific phosphorylation of caspase-3 by CK2alpha': implications for pathological roles of CK2 in promoting cancer cell survival . Oncotarget . 2013 ; 4 : 560 - 71 .
69. Parrish AB , Freel CD , Kornbluth S. Cellular mechanisms controlling caspase activation and function . Cold Spring Harb Perspect Biol . 2013 ; 5 : a008672 .
70. Kronke J , Fink EC , Hollenbach PW , MacBeth KJ , Hurst SN , Udeshi ND , et al. Lenalidomide induces ubiquitination and degradation of CK1alpha in del(5q) MDS . Nature . 2015 ; 523 : 183 - 8 .
71. Piazza FA , Ruzzene M , Gurrieri C , Montini B , Bonanni L , Chioetto G , et al. Multiple myeloma cell survival relies on high activity of protein kinase CK2 . Blood . 2006 ; 108 : 1698 - 707 .
72. Nishida MY , E. CK2 controls multiple protein kinases by phosphorylating a kinase-targeting molecular chaperone, Cdc37 . Mol Cell Biol . 2004 ; 24 : 4065 - 74 .
73. Miyata Y. Protein kinase CK2 in health and disease: CK2: the kinase controlling the Hsp90 chaperone machinery . Cell Mol Life Sci . 2009 ; 66 : 1840 - 9 .
74. Hessenauer A , Schneider CC , Gotz C , Montenarh M. CK2 inhibition induces apoptosis via the ER stress response . Cell Signal . 2011 ; 23 : 145 - 51 .
75. Muller P , Ruckova E , Halada P , Coates PJ , Hrstka R , Lane DP , et al. C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to cochaperones CHIP and HOP to determine cellular protein folding/ degradation balances . Oncogene . 2013 ; 32 : 3101 - 10 .
76. Fernandez-Saiz V , Targosz BS , Lemeer S , Eichner R , Langer C , Bullinger L , et al. SCFFbxo9 and CK2 direct the cellular response to growth factor withdrawal via Tel2/Tti1 degradation and promote survival in multiple myeloma . Nat Cell Biol . 2013 ; 15 : 72 - 81 .
77. Costa F , Vescovini R , Bolzoni M , Marchica V , Storti P , Toscani D , et al. Lenalidomide increases human dendritic cell maturation in multiple myeloma patients targeting monocyte differentiation and modulating mesenchymal stromal cell inhibitory properties: Oncotarget; 2017 . doi: 10 . 18632/oncotarget.18085.
78. An X , Tiwari AK , Sun Y , Ding P-R , Ashby CR Jr, Chen Z-S. BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review . Leuk Res . 2010 ; 34 : 1255 - 68 .
79. Jerkeman M , Hallek M , Dreyling M , Thieblemont C , Kimby E , Staudt L . Targeting of B-cell receptor signalling in B-cell malignancies . J Intern Med . 2017 . doi: 10 .1111/joim.12600.
80. Young RM , Shaffer AL 3rd, Phelan JD , Staudt LM . B-cell receptor signaling in diffuse large B-cell lymphoma . Semin Hematol . 2015 ; 52 : 77 - 85 .
81. Pizzi M , Piazza F , Agostinelli C , Fuligni F , Benvenuti P , Mandato E , et al. Protein kinase CK2 is widely expressed in follicular, Burkitt and diffuse large B-cell lymphomas and propels malignant B-cell growth . Oncotarget . 2015 ; 6 : 6544 - 52 .
82. Quotti Tubi L , Gurrieri C , Brancalion A , Bonaldi L , Bertorelle R , Manni S , et al. Inhibition of protein kinase CK2 with the clinical-grade small ATPcompetitive compound CX-4945 or by RNA interference unveils its role in acute myeloid leukemia cell survival, p53-dependent apoptosis and daunorubicin-induced cytotoxicity . J Hematol Oncol . 2013 ; 6 : 78 .
83. Prins RC , Burke RT , Tyner JW , Druker BJ , Loriaux MM , Spurgeon SE . CX-4945, a selective inhibitor of casein kinase-2 (CK2), exhibits anti-tumor activity in hematologic malignancies including enhanced activity in chronic lymphocytic leukemia when combined with fludarabine and inhibitors of the B-cell receptor pathway . Leukemia . 2013 ; 27 : 2094 - 6 .
84. Martins LR , Perera Y , Lucio P , Silva MG , Perea SE , Barata JT . Targeting chronic lymphocytic leukemia using CIGB-300, a clinical-stage CK2-specific cellpermeable peptide inhibitor . Oncotarget . 2014 ; 5 : 258 - 63 .
85. Chon HJ , Bae KJ , Lee Y , Kim J. The casein kinase 2 inhibitor, CX-4945, as an anti-cancer drug in treatment of human hematological malignancies . Front Pharmacol . 2015 ; 6 : 70 .