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A microRNA Prognostic Marker Identified in Acute Leukemia

A microRNA Prognostic Marker Identified in Acute Leukemia. Introduction. MicroRNAs (abbreviated  miRNA ) are a block of small endogenous non-coding single-stranded RNAs found only in eukaryotic cells. • Small in size with an average length of 22 - 25 nucleotides .

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A microRNA Prognostic Marker Identified in Acute Leukemia

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  1. A microRNA Prognostic Marker Identified in Acute Leukemia

  2. Introduction • MicroRNAs (abbreviated miRNA ) are a block of small endogenous non-coding single-stranded RNAs found only in eukaryotic cells. • Small in size with an average length of 22 - 25 nucleotides. • Transcribed by RNA polymerase II into long primary transcripts • They play important gene-regulatory roles in both plants and animals. • Regulate the expression of over 60% of all human genes . •The majority of miRNAs are located within the cell, some miRNAs, commonly known as circulating miRNAs or extracellular miRNAs, have also been found in extracellular environment, including various biological fluids and cell culture media.

  3. Discovery of miRNAs • In 1993, Ambros and Ruvkun discovered the first microRNA (miRNA) (lin-4) that repressed messenger RNA (mRNA) lin-14 through complementary base pairing in C. elegans. • This complementarity was proposed to inhibit the translation of the lin-14 mRNA into the LIN-14 protein. • It took till 2000 to recognize that this phenomenon was not restricted to worms, but also occurred in mammals.

  4. In 2000 a second small RNA was characterized: let-7RNA, which represses lin-41 to promote a later developmental transition in C. elegans. •  The let-7 RNA was found to be conserved in many species, leading to the suggestion that let-7  RNA and additional "small temporal RNAs" might regulate the timing of development in diverse animals, including humans . • A year later, the lin-4 and let-7 RNAs were found to be part of a large class of small RNAs present in C. elegans, Drosophila  and human cells . •  The many RNAs of this class resembled the lin-4 and let-7 RNAs, except their expression patterns were usually inconsistent with a role in regulating the timing of development. • This suggested that most might function in other types of regulatory pathways. At this point, researchers started using the term “microRNA” to refer to this class of small regulatory RNAs . • The first human disease associated with deregulaton of miRNAs waschronic lymphocytic leukemia.

  5. MiRNA biogenesis

  6. Begins inside the nucleus, then its processing and maturation take place in the cytoplasm of an eukaryotic cell. • MiRNAs are transcribed by RNA polymerase II as long primary transcript (pri-miRNAs) characterized by hairpin structure and then cleaved by the enzyme Drosha in smaller molecules of nearly 70-nucleotides (pre-miRNAs). • These precursors are then exported to the cytoplasm by the Exportin 5/Ran-GTP complex and further processed by RNAse III Dicer, which generates double-stranded-RNAs called duplex miRNA/miRNA* of 22-24 nucleotides.

  7. The strand corresponding to the mature miRNA is incorporated into a large protein complex named RISC (RNA-induced silencing complex) and they interact with the 3' UTR of the targeted messenger RNA: if the complementarity between miRNA and the 3'UTR is perfect the latter is cleaved by RISC, whereas if the matching is imperfect then translational repression occurs.

  8. Reasons to use microRNAs as Biomarkers

  9. Mechanisms of action of miRNAs

  10. MicroRNAs (miRNAs) are involved in the management of hematopoiesis. • As a consequence, miRNA dysregulation causes disruption of the hematopoietic system and leukemia may arise. • These miRNAs are either known miRNAs involved in leukemogenesis with proven tumor suppressor or oncogenic activities or are newly identified with yet unknown function. • However, emerging knowledge about the biology of miRNAs in leukemia may result into a role for these miRNAs in the diagnosis and treatment of acute leukemia. • miRNA expression is also a useful marker to identify disease progression and prognosis.

  11. To date, more than 2500 miRNAs have been identified in the human genome according to latest release of miRBase , but this is still the tip of the iceberg in the world of miRNAs. • miRNAs play important roles incell division, proliferation, differentiation, development, metabolism , apoptosis, immune response and tumorigenesis. • miRNAs participate in these varied cellular processes and involve in the biogenesis and development of many diseases, especially in cancer, by modulating mRNA stability and repressing translation, its potential of serving as diagnostic or predictive biomarkers of disease has become a hotspot in scientific field in the past decades.

  12. The role of microRNAs in gene expression regulation and other processes have been studied in various types of malignant solid tumors. • Many scientists focus their attention on connections between miRNAs and leukemia. • Mir-15a and mir-16 were the first to be proved to have a relation with leukemia as tumor suppressors in chronic lymphocytic leukemia (CLL). • Acute myelocytic leukemia (AML) is the most common subtype of hematological malignancy characterized with poor prognosis and lacks of effective therapeutic targets; miRNAs may give us new insight into AML initiation and provide new ways of therapy.

  13. Acute leukemia • Poorly differentiated blast population. • Rapidly fatal outcome, if untreated. • Is a result of:- • Malignant transformation of a stem cell leading to unregulated proliferation and Arrest in maturation at the primitive blast stage. Acute Leukemia differentiation block enhanced proliferation +

  14. AML ALL

  15. MicroRNA expression signatures accurately discriminate ALL from AML .

  16. To understand the distinct mechanisms in leukemogenesis between ALL and AML and to identify markers for diagnosis and treatment, we performed a large-scale genome-wide microRNA (miRNA) expression profiling assay and identified 27 miRNAs that are differentially expressed between ALL and AML. • Six (i.e., miR-128a, miR-128b, miR-151*, j-miR-5, miR-130b, and miR-210) were ex-pressed at a significantly higher level in ALL than in AML. • Incontrast, the remaining 21 (i.e., let-7b, miR-223, let-7e, miR-125a, miR-130a, miR-221, miR-222, miR-23a, miR-23b, miR-24, miR-27a, miR-27b, let-7a, let-7c, miR-199b, miR-26a, miR-335, miR-21, miR-22, miR-424, and miR-451) • were expressed at a significantly higher level in AML compared with ALL.

  17. a specific miRNA signature of 4 miRNAs is able to distinguish the two forms of acute leukemias (ALL from AML) with an accuracy rate of 98%.  • Indeed, higherexpression of miR-128a and miR-128b was found in ALL compared to AML, whereas down-regulation of let-7b, miR-223 indicates ALL VS AML. • They are the most discriminatory miRNAs between ALL and AML. • At the moment, the leukemogenic mechanism of miR-128b is still poorly understood. • we showed that expression signatures of as few as two miRNAs could accurately discriminate ALL from AML, and that epigenetic regulation might play an important role in the regulation of expression of miRNAs in acute leukemias.

  18. miRNA signature in children with ALL complicated by central nervous system (CNS) relapse. • The high-risk-of-relapse signature is composed of over-expression of miR-7, miR-198, and miR-663, and down-regulation of miR-126, miR-345, miR-222, and miR-551a. • MiR-16 has a prognostic significance in ALL. • low expression of miR-16 is associated with a better ALL outcome. • ALL has a better prognosis than AML.

  19. Prognosis • Cure is a realistic goal for both ALL and AML, especially in younger patients. Prognosis is worse in infants and the elderly and in those with hepatic or renal dysfunction, CNS involvement, testicular involvement, myelodysplasia, or a high WBC count (>25,000/μL). • Survival in untreated acute leukemia generally is 3 to 6 months . • Prognosis varies according to multiple variables including patient age, karyotype, response to therapy, and performance status.

  20. AML

  21. ALL

  22. MiRNAs as Potential Therapeutic Targets and Tools • Because they can function as oncogenes or tumor suppressor genes in leukemogenesis , miRNAs also have the potential to serve as therapeutic targets or tools. • miRNA -based cancer gene therapy offers the theoretical appeal of targeting multiple gene networks that are controlled by a single, aberrantly expressed miRNA. • However, there are still many issues to be resolved prior to consideration of conducting miRNA - based clinical therapy including dosage, efficacy, functionality, delivery, non-specific toxicity, and immune activation.

  23. In addition, because of the redundancy of some miRNA families or functional redundancy of a set of miRNAs that are not in a family, targeting a single member might not be sufficient in terms of gene therapy. • In such cases, targeting several miRNAs simultaneously would be critical. • Furthermore, some miRNAs may play a different role (as oncogene or tumor suppressor) depending on the cellular context. • For example, the mir-17-92 cluster is a well-known oncogene in various types of cancersincluding leukemia, but may it function as a tumor suppressor gene in breast cancer. • Therefore, before considering a potential clinical application, it is important to understand the expression pattern and potential role of the candidate miRNA(s) in other tissues to avoid causing undesirable side effects.

  24. Conclusions • The discovery of miRNAs as powerful regulators of gene expression shed a new light on our understanding of acute leukemia. • It became evident that leukemia is not only a disease of dysregulated protein-coding genes. • In contrast, the biology of acute leukemia involves also dysregulation of the regulators of these genes, that is, miRNAs. • Unique miRNA expression patterns were found for different genetic, prognostic, mutational and drug-resistant subtypes of acute leukemia. • miRNAs were discovered as small biological players but despite their small size their impact on diseases like acute leukemia seems to grow with every miRNA-related publication. • Aberrant expression and function of oncogenic and tumor suppressive miRNAs may contribute to the biology of diverse leukemia subtypes. • Therefore, these small biological players may become clinical contributors in the diagnosis and treatment of acute leukemia.

  25. In summary, we have highlighted a broad network of miRNA expression in human leukemia. • Some have oncogenic activity while others a have tumor suppressive role. • What needs to be explored next is whether we have the technology to target these dysregulated miRNA in a clinical disease setting such as leukemia. • Alternatively, if this is an unworkable strategy we could use the expression profiling to inform the clinic on diagnosis and prognosis of the disease, or maybe allow for more targeted chemotherapy treatment.

  26. References • http://2.micancerna.appspot.com/mir128-leukemia.html • http://www.smartscitech.com/index.php/RD/article/view/540 • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543150/ • http://www.sciencedirect.com/science/article/pii/S0167488910001837 • https://www.ncbi.nlm.nih.gov/pubmed/27179712

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