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marrow niche, including bortezomib, lenalidomide and other immunomodulatory drugs, has significantly
changed treatment strategies in MM and improved patient outcomes. Importantly, some of these agents can
have dual effects, reducing MM growth and mitigating the deleterious effects of MM cells on bone [20,21] .
Notch signaling, a pathway mediating the communication between adjacent cells, has been identified as
aberrantly activated in the MM tumor niche. In this manuscript, we review the last findings and pleiotropic
effects of Notch signaling activation in MM and discuss new advances in the therapeutic strategies aiming to
target Notch for the treatment of MM and the associated bone disease.

THE NOTCH SIGNALING PATHWAY
Notch is a highly conserved signaling pathway that mediates short-range, cell-to-cell communication
[Figure 1] [22-24] . In fact, under most circumstances, Notch signaling transmission requires physical contact
between cells. The Notch pathway core components include Notch transmembrane receptors (1-4), 2
families of membrane-bound ligands, Delta-like ligands (Dll) 1-4 and Serrate-like ligands (Jagged) 1 and 2,
the Notch receptor proteases Adam and γ-secretase, and the nuclear effector Csl (also known as Cbf1 or
RbpjK) [22-25] . The Notch membrane-bound ligands are expressed in signal-sending cells. Notch ligands are
type I transmembrane proteins with 3 main structural domains: a N-terminal DSL motif, a specialized
tandem EGF repeat called the DOS domain, and EGF-like repeats [26,27] . Both the DSL and the DOS domains
are involved in receptor binding [26,27] . Notch receptors, expressed in the signal-receiving cell, are single-pass
type I transmembrane proteins and can have both redundant and unique functions. The extracellular
domain of Notch receptors is required for ligand binding [28,29] . Notch receptors do not have enzymatic
activity and rely on a sequence of proteolytic cleavage events to become active [30,31] . When the Notch ligand
and receptor come into contact, there is a conformation change in the extracellular portion of the Notch
receptor, which unmasks the cleavage site 2 (S2). This allows for Adam metalloproteases, Adam10 and
[32]
Adam17, to cleave the Notch receptor at the S2 cleavage site, the first step leading to its activation . After
[32]
S2 cleavage, the γ-secretase complex cleaves at site 3 (S3) . This cleavage causes the separation of the C-
terminal portion of the receptor, known as NICD, which is now free to translocate to the nucleus. In the
absence of NICD, RbpjK is bound to co-repressor proteins to prevent transcription [Figure 1]. Once in the
nucleus, the NICD displaces the co-repressors and interacts with RbpjK, as well as recruits mastermind-like
(MAML) proteins to form a multi complex that induces transcription of various genes downstream [33,34] .
Notch target genes include genes in the hairy and enhancer-of split (Hes) and hairy and enhancer-of-split
with YRPW (Hey) families, which are helix-loop-helix proteins that function as transcriptional
[35]
regulators . This limited set of target genes is believed to mediate the diverse biological outcomes
downstream the activation of Notch receptors.

Notch has pleiotropic biological functions, which are both context and cell dependent [22,23,36] . For instance,
Notch signals mediate essential biological processes, including cell differentiation, apoptosis, proliferation,
cell fate, and differentiation programs in both development and maintenance of adult tissues . Given its
[25]
relevant role in fundamental biological processes, aberrant Notch signaling underlies the pathophysiology of
several human disorders , including solid and hematological cancers [36,37] .
[24]
DYSREGULATION OF NOTCH SIGNALING IN MULTIPLE MYELOMA
It is well documented that the Notch signaling pathway is deregulated in MM and preclinical data suggest it
contributes to the progression of MM [25,38,39] . Analysis of immunostainings for Notch components in bone
marrow biopsies from MM patients and healthy subjects revealed that the expression of Notch receptors 1
and 2 is increased in malignant plasma cells from MM patients compared to nonmalignant plasma cells or
bone marrow from healthy individuals [40-42] . Notch receptor 3 expression is low in MM cells . To the best of
[43]
our knowledge, no studies have been conducted to determine if the expression of Notch receptor 3 is