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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 71

factor 2). As ILF2 is a key regulator in HR repair in MM, high ILF2 expression promotes resistance to
genotoxic reagents by modulating the translocation of YB1 (Y-box binding protein 1). Therefore, blocking
[98]
the ILF2 signaling pathway may improve the effect of DNA-damaging agents in MM therapy .

Deregulated plasma cell differentiation
IRF4 (interferon regulatory factor 4), also known as MUM1, is involved in the regulation of interferon
[14]
transcription and B cell proliferation and differentiation . An in vitro RNA-interference study discovered
that IRF4 is necessary for the survival of MM cell lines . IRF4 is also important therapeutically, as the
[99]
backbone MM drug lenalidomide indirectly downregulates IRF4 by downregulating cereblon, the primary
target of the CRBN-IKFZ1/3-IRF4-MYC pathway [100,101] . IRF4 acts as a transcription factor for BLIMP1,
another transcription factor pivotal in plasma cell differentiation. A study by Chapman et al. identified 2
[7]
out of 38 patients with MM harboring an identical mutation (K123R) in the DNA-binding domain of IRF4.
The same study group also harbored loss of function mutations in BLIMP1 usually identified in diffuse large
B-cell lymphoma [7,102] . However, the role of differentiation pathway dysfunction in myelomagenesis needs
further investigation as MM is a malignancy of terminally differentiated plasma cells.

Bone disease in myeloma
Bone disease in MM is associated with shorter overall survival and presents as focal/diffuse pain,
pathological fractures, cord compression, and hypercalcemia. It is common in patients with hyperdiploidy,
t(4;14), and MAF translocations . A recent GEP study has identified approx. 50 genes linked with bone
[103]
disease, with DKK1 and FRZB being the most prominent. DKK1 and FRZB are Wnt pathway inhibitors and
induce osteoblast differentiation inhibition and increase bone resorption via RANKL/OPG ratio
imbalance [104,105] . The antibody against DKK1 is an important therapeutic area to approach bone disease in
MM patients. Anti-DKK1 antibody has resulted in improved bone disease outcomes and myeloma cell
[106]
growth inhibition in pre-clinical models .

EPIGENETIC MODIFICATIONS
First, genomic instability is the hallmark of MM, and dysfunctional DNA damage response is one of the
many driving contributing factors . SIRT6 (NAD-dependent deacetylase) is highly expressed in MM cells
[3]
and is linked with poor prognosis. Its expression is an adaptive response to maintain genomic stability.
SIRT6 interacts with the promoter area of transcription factor ELK1 and ERK signaling-related genes. SIRT6
also downregulates the MAPK pathway gene expression and signaling. Moreover, the inactivation of ERK2
[107]
signaling increases DNA repair via checkpoint kinase 1 and confers resistance to DNA damage . RecQ
helicase, a DNA unwinding enzyme, is involved in maintaining chromosome stability. MM cells have a
higher expression of RECQ1, which is associated with poor prognosis. RECQ1 over-expression helps MM
cells escape from cytotoxicity of melphalan and bortezomib. On the contrary, knockdown of RECQ1
suppresses cell growth and stimulates apoptosis in MM cells; RECQ1 depletion promotes double-strand
breaks on DNA in MM cells and sensitizes them to PARP inhibitors. RECQ1 downregulation can also be
induced by DNMT inhibitor treatment through dysregulation of miR-203 in MM. Hence, PARP inhibitors
combined with DNMT inhibitors constitute an important therapeutic approach for MM patients [3,108] .

The HOXA9 gene encodes a DNA-binding transcription factor involved in cell differentiation,
morphogenesis, and gene expression regulation. It is regulated by histone methyltransferases, and
knockdown of it in MM cell lines incurs a competitive disadvantage as compared to those with intact
HOXA9 gene expression. This indicates the role of HOXA9 expression in myelomagenesis and the
utilization of epigenetic changes for devising new therapeutic targets in MM .
[7]