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428 Malakar et al. | Journal of Clinical and Translational Research 2023; 9(6): 423-432
the category of trans-acting RNA binding proteins [51,53]. It is drug response of selinexor (Figure 1C). The objective would
worth noting that only a limited number of RNA-binding proteins be to investigate how aberrant alternative splicing impacts the
have been associated with childhood ALL. In addition, their effectiveness of selinexor in the treatment of childhood ALL.
precise contributions to childhood ALL are still emerging. The
phenomenon of alternative splicing is deregulated in AML [22]. 6. Long Noncoding RNAs
Aberrant spliced Isoforms of IKZF1 have been detected not only Long non-coding RNAs (lncRNAs: longer than 200 nucleotides)
in leukemic cell lines but also in samples derived from patients play a crucial role in regulating various aspects of gene expression.
with ALL [54]. Furthermore, the splicing patterns of IKZF1 have They are involved in processes such as chromatin remodeling,
been associated with the development of resistance to receptor transcriptional control, regulation of splicing, mRNA stability,
tyrosine kinase inhibitors among samples from ALL patients [55]. mRNA translation, miRNA processing, and protein stability [62].
Likewise, a connection has been established between the splicing Recently, a study has shed light on the involvement of lncRNAs
of isoforms in the N terminus of p53 and its involvement in in the etiology, progression, and treatment response of childhood
ALL [56]. In AML, a particularly noteworthy aspect involves ALL [63]. In addition, MALAT1, a specific long noncoding RNAs
the recurrence of mutations within the machinery responsible has been linked to poor prognosis in childhood AML [64]. Multiple
for splicing, leading to widespread instances of irregular splicing studies have also implicated MALAT1 in drug resistance of
events across the entire genome [57]. Studies looking at the role various cancer types [65-70]. It would be intriguing to investigate
of spliceosome machinery and aberrant splicing have not been the expression of MALAT1 in response to selinexor exposure
studied extensively in childhood ALL. One of the most critical in childhood ALL cell lines and patient samples. This raises
challenges in contemporary cancer treatment is the emergence of the question of whether MALAT1 plays a role in determining
resistance to therapeutic medications, ultimately culminating in the sensitivity of selinexor. Furthermore, it is worth noting that
the failure of treatment endeavors [10,58]. Importantly, alternative MALAT1 is a nuclear-localized lncRNA, while selinexor acts as an
splicing holds the capacity to significantly alter the coding region inhibitor of nuclear export. The impact of selinexor on MALAT1
of drug targets [57]. expression, function, and regulation remains unknown.
Several reports have identified significant alternative splicing
p53, a well-studied tumor suppressor protein, has been
events that take place in different types of cancers and contribute demonstrated to govern the expression of several lncRNAs,
to resistance against cancer therapies [59]. In the context of Phase including lncRNA-p21 [71], PANDA [72], DINO [73], and
II clinical trials targeting patients with myelodysplastic syndrome PURPL (p53 upregulated regulator of p53 levels), [74]. PURPL
(MDS), the administration of selinexor resulted in mixed is an intergenic lncRNA that was identified by RNA sequencing
outcomes, with some patients showing a positive response while (RNA-seq) in multiple colorectal cancer (CRC) lines [74]. The
others did not respond [19]. Genetic investigations have revealed loss of PURPL has been linked to elevated basal levels of p53 and
a strong connection between the response to selinexor and the an impairment of cell growth both in vitro and in vivo [74]. Recent
presence of hotspot mutations within the core RNA splicing factor
SF3B1 [60]. Notably, SF3B1 mutations are frequently found research has shown that PURPL production is transcriptionally
in MDS and render cells more vulnerable to the impairment of regulated by the transcription factor p53, which tends to be elevated
normal splicing functions in remaining wild-type genes. This in senescent conditions [75]. Given the dependency of selinexor
interplay between SF3B1 mutations and the response to selinexor sensitivity on p53 levels observed in AML [13], it becomes
is particularly significant, given SF3B1’s established association intriguing to investigate the levels of p53-regulated lncRNAs in
with MDS and the essential role of XPO1 in the nuclear export and ALL. In addition, selinexor treatment has been shown to lead to an
maturation of RNA spliceosome components [61]. After selinexor increased accumulation of p53 inside the nucleus [13]. However,
treatment, comprehensive transcriptomic sequencing of alternative the impact of selinexor on well-established p53-targeted lncRNAs
splicing events in bone marrow specimens taken before and after such as lncRNA-p21, PANDA, DINO, and, PURPL, in terms
treatment unveiled a distinct pattern [61]. Patients who achieved of their expression, function, and regulation, remains largely
marrow complete remission (mCR) displayed a widespread unknown (Figure 2A). In addition, the role of p53-regulated
disruption in RNA splicing, characterized by heightened intron noncoding RNAs in childhood ALL remains unexplored.
retention (IR) in post-treatment samples compared to their pre- 7. Summary and Future Prospectives
treatment counterparts. In contrast, those who did not achieve
mCR exhibited less pronounced IR [61]. Due to the extensive disruption of nuclear transport in cancer
Interestingly, selinexor induced significant IR, notably in the and its pivotal involvement at the crossroads of crucial signal
Inhibitor of NF-kB Kinase Subunit Beta gene. This led to the transduction pathways, there has been a significant focus on
inclusion of a premature stop codon, subsequently triggering exploring exportins as a prime target in cancer-related research.
nonsense-mediated decay and disrupting the NF-kB signaling A plethora of small molecules targeting XPO1 inhibition have
pathway [61]. These observations became apparent when closely been discovered. In preclinical investigations, the administration
examining the most prominent instances of IR among selinexor of selinexor leads to the suppression of XPO1, leading to the
responders [61]. Considering the above observations, it would accumulation of its target molecules within the nucleus. The
be intriguing to explore the role of alternative splicing in the potential alternations in mTOR signaling, cancer glucose
DOI: http://dx.doi.org/10.18053/jctres.09.202306.23-00088