The use of 5′ splice donor sites (alternative

The human MYC genes belong to the family of oncogenes and
proto-oncogenes and play a significant role in the development of tumors 1-5 that causes deaths of 100,000 million people
worldwide every year. These genes have three
well-characterized members; c-myc, N-myc, and L-myc genes, which code for
nuclear DNA binding phosphoproteins. Indeed, several studies have demonstrated the role
in MYC gene in tumorigenesis, apoptosis, metastasis,
and drug resistance 6,7. L-MYC and N-MYC were identified as amplified, myc homologous DNA
sequences in cell lines from neuroblastoma (N-myc) 8,9 6,7  and human small cell lung carcinoma (L-myc)
10. The L-myc and N-myc
genes have  three-exons which have
similarities with c-myc gene.. The MYC genes are differentially regulated where c-myc is
active in almost all proliferating cell 11-15. L-myc is expressed in developing brain, kidney,
spleen, thymus, pancreas, lung, and skin whereas N-myc has not expression in
these tissues 16-19. Importantly, L-Myc expression is very
low in adult bone marrow and in fetal spleen and thymus. It is composed of three exons and two introns spanning in
human DNA. In case
of, Acute Myelogenous Leukemia (AML), L-Myc process with a unique pattern that lack exon III and intron I 20.  Different mRNA transcripts are generated in cell lung
growth cell lines that express L-myc. These transcripts are produce with
alternative splicing of introns 1 and 2 and by use of alternative
polyadenylation signals. In a
few mRNAs there is a long ORF with an anticipated deciphered protein of 364
amino acids having reliable homology with the c-myc and N-myc. interestingly, other mRNA
transcripts, produced by elective processing, could encode a truncated protein
with a novel carboxy-terminal end. However, the
functional role splicing variants in leukemogenicity has not been defined yet. Two isoforms of Kit transcripts created through the
alternate use of 5′ splice donor sites (alternative splicing) are detected in
AML 21. But further analysis of these demonstrated no apparent association
with pathology of AML 22. An alternatively spliced IL-6R mRNA, encoding soluble IL-6R (sIL-6R)
expressed in 64% of the primary blast cells of AML patients which supports the
evidence of alternative splicing as a mechanism of sIL-6R production in AML
23. Precursor mRNA or
pre-mRNA splicing is  a critical  step in regulation of post-transcriptional
gene expression that provides significant expansion of the functional proteome.
splicing and splicing are markedly affects by the mutations within the
cis-acting elements. These elements are important for correct pre-mRNA
processing. Alternative splicing markedly affects the human development and its
misregulation underlies many human diseases and its misregulation can be more subtle contributions to the
determinants of disease susceptibility 24. It
is believe that 94% of human genes are alternatively spliced and of which  50% of disease causing mutations affect the
splicing process which is carried out by the spliceosome that recognize certain
conservative recognition sites within the exonic and intronic sequences.
The variations and their effects in splice sites of L-MYC gene have not
been deeply addressed. The past decade has seen numerous developments in the field of in silico splicing prediction and can be benefited from the new
generation in silico research tools. There are several free or commercially
available tools today that fulfill the various needs of the splicing process. Therefore, for the first steps
this study will utilize the use of an in
silico system to analyze the various mutations affecting the splicing
mechanism of L-MYC mRNA.


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