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Sadaf et al. J Transl Genet Genom 2022;6:63-83 https://dx.doi.org/10.20517/jtgg.2021.36 Page 69

[14]
adverse prognostic markers . Del 8p downregulates the TRAIL gene. TRAIL gene is linked with TNF-
induced apoptosis. Its downregulation facilitates the immune escape of malignant clones from cytotoxic T
[74]
lymphocytes and natural killer cells .

DEREGULATED CELLULAR PATHWAYS
Several signaling pathways are dys-regulated in MM and contribute towards pathogenesis by influencing
proliferation, apoptosis, survival, migration, and drug resistance .
[75]
NF-κB pathway
NF-κB is a group of transcription factors that play important roles in cell proliferation, differentiation, and
[76]
survival, as well as in inflammation and immunity . The NF-κB pathway is active in 50% of MM cases and
[77]
involves both plasma cells and bone marrow stromal cells (BMSCs) . Activation of NF-κB within MM cells
involves either activation of oncogenes or inactivation of tumor suppressor genes in the pathway . Genes
[78]
encoding components of the NFκB pathway include TRAF3, CYLD, LTB, IKBKB, CARD11, BIRC2, BIRC3,
and TRAF3IP1 . The NF-κB pathway does not influence the survival in MM . The pathway involves the
[54]
[14]
[78]
proteasome protein complex, thereby suggesting the role of proteasome inhibitors in MM treatment .
Cell proliferation pathways
The cell proliferation pathways in MM include the MAPK pathway, the JAK-STAT pathway, and the
phosphatidylinositol-3 kinase (PI3K) pathway.

The MAPK pathway
The MAPK pathway is a chain of proteins that communicate signals from cell surface receptors to the DNA
[79]
in the cell nucleus . The pathway is activated from inflammatory cytokines TNF-a, IL-6, and IGF-1 and, in
return, triggers the downstream kinase cascades RAS, RAF, MEK, and MAPK, thus regulating gene
expression. Two dominant oncogenes involved in this pathway include NRAS and KRAS . Their mutations
[80]
are frequently subclonal and are involved in disease progression. RAS mutations indicate a poor prognosis,
aggressive phenotype, and shortened survival . The involvement of RAS mutations across various cancers
[51]
has given insight into the research on therapeutic inhibitors within this area . Likewise, activation of
[14]
mutation in the BRAF-MAPK signaling pathway, which encodes serine/threonine-protein kinase suggests
the potential use of BRAF inhibitors in MM patients with BRAF mutations .
[81]
The JAK-STAT pathway
The JAK-STAT pathway is activated in both MM cells and BMSCs in approximately 50% of cases .
[82]
[14]
Cytokine IL-6 signaling induces JAK-STAT activation and myelomagenesis . The over-activation of
STAT3, a STAT family transcription factor, causes over-expression of Bcl-x an anti-apoptotic protein, and
therefore triggers chemoresistance . The in vitro inhibition of STAT3 with atiprimod, curcumin, and the
[83]
JAK2 kinase inhibitor AG490 have already shown fair results for inhibition of IL-6-induced MM survival .
[84]
In addition, STAT3 inhibition has shown sensitization of the U266 cell line to apoptosis from conventional
chemotherapy agents . Hence, these results highlight the prospective conjoined role of STAT3 inhibitors
[85]
and conventional chemotherapy in myeloma treatment .
[14]
The PI3K pathway
PI3K-Akt is a signal transduction pathway that supports cell growth and survival in response to extracellular
[86]
signals . The PI3K (phosphatidylinositol 3-kinase) gets activated with IL-6 and IGF-1 action on tyrosine
kinase receptors, leading to phosphorylation of the serine-threonine-specific kinase AKT (serine/threonine
kinase). AKT, in return, activates its downstream genes, including mTOR, GSK-3B, and FKHR, therefore