Page 151 - Read Online

Page 70 Sadaf et al. J Transl Genet Genom 2022;6:63-83 https://dx.doi.org/10.20517/jtgg.2021.36

[14]
regulating cell proliferation and apoptosis resistance . The phosphorylated AKT is a marker indicative of
[87]
pathway activity, which is observed in approximately 50% of MM cases . Therapeutic targeting of PI3K is
[14]
an area of interest in MM research .
Cell cycle deregulation
The deregulation of the G1/S cell cycle transition point via cyclin D gene overexpression is central to an
[14]
early molecular abnormality in MM . Additionally, the defect of negative cell cycle regulatory genes is
another major event that destabilizes cell cycle regulation. CDKN2C (Cyclin-Dependent Kinase Inhibitor
[68]
2C) downregulation either by 1p deletion or DNA methylation deregulates the G1/S transition . Similarly,
CDK inhibitors p15, p16, and p18 are important in the regulation of progression through the cell cycle.
Studies have shown that hypermethylation and homozygous deletions of p15, p16, and p18 genes lead to
uncontrolled growth and MM progression . Treatment with the demethylating agent 5-deoxycytidine
[88]
restores p16 protein expression and induces G1 growth arrest in MM cell lines . p21, another potent
[75]
cyclin-dependent kinase inhibitor, binds to and inhibits the activity of CDK2, CDK1, and CDK4/6
complexes. It protects the MM cells from apoptosis by the induction of cell cycle arrest and subsequent
[89]
DNA repair, hence inducing resistance to apoptosis by chemotherapy and radiotherapy . Furthermore,
RB1 (tumor suppressor gene) inactivation also affects the G1/S transition and may occur because of
monosomy 13, homozygous deletion, or mutational inactivation .
[57]
Defective DNA repair
The DNA repair score is a predictive factor for progression-free and overall survival of MM patients. The
score’s strength is based upon the influence of aberrant DNA repair in MM . The understanding of DNA
[90]
repair mechanisms in MM is important for developing therapeutic approaches based on the concept of
synthetic lethality. It states that a combination of deficiencies in two genes (e.g., gene X and a DNA repair
gene) causes cell death, whereas a deficiency in only one of the genes (gene X) does not . For example, poly
[3]
ADP-ribose polymerase (PARP) inhibitors are used to treat solid tumors deficient in BRCA1 and BRCA2
function, which are important for maintaining the error-free homologous recombination (HR) pathway of
DNA repair. PARP is a family of proteins involved in several cellular processes (e.g., DNA repair, genomic
stability, and programmed cell death). PARP1 expression is linked with shortened survival and high-risk
[91]
disease in MM patients . PARP inhibitors have given promising results in cancers with defective HR-
mediated DNA repair mechanisms, as MM backbone drugs proteasome inhibitors (e.g., bortezomib) affect
the apoptotic sensitivity of MM cells . Therefore, bortezomib-induced impairment of homologous
[91]
recombination in MM cells can pharmacologically sensitize them to PARP inhibition, resulting in synthetic
[91]
lethality . We recently found that a noncoding RNA MALAT1 is critical for PARP1 binding to LIG3 to
mitigate an alternative end-joining DNA repair pathway and may serve as a novel therapeutic target for
MM [92,93] .

Abnormal RNA editing
Post-transcriptional RNA processing is important for the maintenance of genomic stability in MM . MM
[94]
patients may harbor mutations in genes controlling RNA processing and protein translation. DIS3 gene on
13q22.1 encodes an exonuclease involved in regulating the abundance of RNA species. In MM patients, loss
of DIS3 function is linked to monoallelic mutation or deletion. Exosomes play a vital role in regulating the
mRNA pool. Therefore, loss of DIS3 activity may contribute to oncogenesis of MM due to protein
translation deregulation. Similarly, the role of FAM46C in translational control and recurrent mutation in
myelomagenesis is of biological relevance . RNA processing includes splicing pattern modification of
[95]
transcripts involved in DNA repair . This alternative splicing of DNA repair depends upon the proper
[96]
activity of RNA-binding proteins (RBPs) . Genetically aggressive myeloma patients who have 1q21
[97]
amplification usually have 1q21-induced over-expression of the RBP-ILF2 (interleukin enhancer-binding