Introduction:
In 2020, leukemia was reported in around 60,500 people in the USA, and more than 23,000 patients died. The incidence of leukemia is still increasing, and the main concern is the development of drug resistance. During the past two decades, studies have been conducted on small non-coding RNAs to evaluate their functions and possible role in cancer pathogenesis.
Small non-coding RNAs are short RNA (ribonucleic acid) molecules used in several cellular processes regulating gene expression. Various independent studies show that the expression of these genes is tissue-specific, and the dysregulation alters the gene expression in tumor development, progression, and drug response.
The small non-coding RNAs play an essential role in the staging, onset, relapse, and drug response of hematological malignancies and cancers. These findings strongly suggest that small non-coding RNAs usually function as biomarkers and possible targets for therapy. A path-breaking event in the development of chronic lymphocytic leukemia (CLL) is the deletion of the encoded genomic region for miR-15a/16-1.
What Is Leukemia?
Leukemia results from the accumulation of underdeveloped leukocytes in the blood and bone marrow. Leukemia has been traditionally classified into various groups:
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Acute or chronic (based on clinical presentation).
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Lymphocytic or myelogenous (based on cell of origin lineage).
Acute leukemia occurs as a result of the rapid onset of symptoms and leads to the accumulation of poorly differentiated blast cells. On the contrary, chronic leukemia progresses slowly with a gradual onset of symptoms. It is characterized by the accumulation of more mature yet dysfunctional cells.
The major subtypes of leukemia are classified into the following four classes:
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Chronic lymphocytic leukemia (CLL) is the most common type of human leukemia that causes the accumulation of incompetent CD5+ B lymphocytes. Most CLL cases are seen primarily in elderly patients.
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Acute lymphocytic leukemia (ALL) occurs as a result of a family of genetically heterogeneous lymphoid neoplasms derived from B and T lymphoid progenitors. Most of the patients are children where the lymphoid blasts replicate without developing into normal B and T cells.
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Acute myeloid leukemia (AML) is a heterogeneous clonal disorder caused due to the proliferation of myeloid blasts and bone marrow failure and is the most common acute leukemia in adults.
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Chronic myeloid leukemia (CML) is developed as a result of clonal myeloproliferative expansion of transformed hematopoietic myeloid cells of erythroid, monocytic, and megakaryocytic lineages. CML cases occur mostly in individuals between the ages of 25 and 60.
What Are MicroRNAs?
MicroRNAs are tiny non-coding RNAs used to regulate gene expression and loss of miR-15a/16-1 in CLL. It leads to the accumulation of the antiapoptotic gene BCL2 and inhibits the apoptotic process. This finding supported that microRNAs play a role in the onset of cancer.
After this finding, various studies were conducted to investigate the role of microRNAs and other small non-coding RNAs in various types of leukemia and cancers.
What Is the Role of RNA in Leukemia?
B cell chronic lymphocytic leukemia (CLL) is the most commonly occurring human leukemia in the Western world. CLL can be seen in aggressive or indolent form. Both these forms are characterized by the accumulation of CD5+ B lymphocytes with certain genetic abnormalities. Unfavorable prognoses are associated with a prognostic marker like a high expression of unmutated immunoglobulin heavy variable genes (UM-Ig-VH) and a high level of 70 kD zeta-associated protein (ZAP70).
Further, chromosomal changes are identified in more than 80 percent of cases and are used to classify patients into risk groups:
(i) Low Risk: Normal karyotype or 13q deletion.
(ii) Intermediate Risk: 11q deletion or trisomy 12.
(iii) High Risk: 17p deletion or complex karyotype.
The study of small non-coding RNAs is also essential for the discovery of new targets for therapy. The development of new drugs to be used in combination for synergistic effects is vital for designing therapeutic strategies which can further prevent drug resistance onset. Certain observations helped to discover that microRNAs have a key role in the following:
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Fine-tuning of gene expression.
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Affects cell survival.
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Apoptosis.
In 1984 the identification of the BCL2 translocation and in 2005, the description of the miR-15a/16-1-mediated post-transcriptional mechanism led to the fundamentals for initiating the development of one of the most efficient drugs for the management of CLL, Venetoclax. Further, it was discovered that miR-15a/16-1 targets ROR1 (an onco-embryonic surface protein) that is shown in CLL cells but not found in normal cells.
Currently, Cirmtuzumab (an anti-ROR1 monoclonal antibody) is being evaluated for treatment, and it has shown a synergistic effect with the in vitro cytotoxic activity of Venetoclcax. The miR-15a/16-1 is often significantly downregulated in other hematopoietic malignancies and various types of cancers. In fact, most patients with AML exhibit a downregulation of either miR-15a/16-1 or miR-15b/16-2, and around 21 percent of AML patients exhibit a downregulation in both.
These AML patients must be considered for the management of Venetoclax, alone or in combination with Cirmtuzumab. A correlation between the expression of miR-15a/16 and the transition of CML from the chronic phase to the blastic phase has also been reported indicating that the expression of these miRs is reduced during the disease progression while their targets are overexpressed. Thus, the loss of both miR-15/16 clusters is an important event in the transition from the chronic phase to blast crisis, and CML patients must also be considered for combination therapy with Venetoclax and Cirmtuzumab.
Various other microRNAs have been found dysregulated in leukemia and help in disease progression, classification, and treatment response. For instance, the miR-181 family members are dysregulated in various types of leukemia. Downregulation of miR-181b is an important indicator of disease progression in CLL patients, and miR-181b has been reported as a possible therapeutic agent for CLL.
Conclusion:
The study of small non-coding RNAs has shown outstanding results in the management of cancer. With the identification of new markers for differential diagnosis, there has been an improvement in the classification of patients for a more effective treatment. Further, small non-coding RNAs can be used to monitor disease progression and initiation of drug resistance.
