**Small Non-Coding RNAs in Regulation of Course and Therapeutic Efficacy in Acute Myeloid Leukemia Therapeutic Efficacy in Acute Myeloid Leukemia**

**Small Non-Coding RNAs in Regulation of Course and** 

DOI: 10.5772/intechopen.70931

Oxana V. Klimenko Oxana V. Klimenko Additional information is available at the end of the chapter

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84 Myeloid Leukemia

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70931

#### **Abstract**

Small non-coding RNAs (sncRNAs) are small regulatory molecules, which play key roles in fine-tune of all cell functions. In late 1970s and early 1980s, it was first determined that non-coding RNAs contribute to the cellular regulatory processes. The kingdom of sncRNAs is very numerous and it is clear that functions of different members of this family is different from each other and may be involved in normal and pathologic processes in cell. Recently it was investigated that sncRNAs and long non-coding RNAs play roles in cellular differentiation, proliferation, metabolic processes, bioenergetic regulation, cell death and inter-cellular communications, etc. In embryos, non-coding RNAs control maternal-zygotic transition, the maintenance of pluripotency, the pattering of the body axes, the specification and differentiation of cell types and morphogenesis of organs. Development of hematologic malignancies in humans, their course and regulation of resistance and sensitivity of tumorous cells to therapy are under the control of sncRNAs.

**Keywords:** small non-coding RNAs, micro-RNAs, antago-miRNA, nano-sized polymer carriers, leukemic cell transformation

### **1. Introduction**

#### **1.1. Small non-coding RNAs**

Small non-coding RNAs (sncRNAs) are oligonucleotides with length less than 200 nt. This is numerous family of non-coding genomic regulators. The most investigated sncRNAs are micro-RNAs (miRNAs) and small interfered RNAs (siRNAs). Less studied sncRNAs are piwi-interacting RNAs (piRNAs), small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs) [1, 2].

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

#### **1.2. Biogenesis of micro-RNAs and piwi-interacting RNAs**

All small non-coding RNAs before they become functionally active undergo different processes of biogenesis from their precursor form. This multistep maturation is necessary for normal functionality of small non-coding RNAs. Imbalance of one or more steps of sncRNAs biogenesis may results in development of different pathologic disorders and carcinogenesis [3].

amplification loop model of piRNA biogenesis, antisense piRNAs in complex with Aub directly cleaves sense-strand transposon sequences, generating sense piRNAs for Ago3. The Ago3-piRNA complex then directs cleavage of antisense piRNA precursors, generating antisense piRNAs for Aub. The 5′-ends of amplified secondary piRNAs are determined by Aub

Small Non-Coding RNAs in Regulation of Course and Therapeutic Efficacy in Acute Myeloid…

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sncRNAs may play double-faced roles in carcinogenesis as oncogenes and tumor suppressors. As oncogenes sncRNAs function in tumor initiation, progression and resistance to therapies; as tumor suppressors, sncRNAs inhibit cell growth, induce apoptosis, block cell cycle and promote cell differentiation [26, 27]. In every pathologic condition, its own biomarker sncRNAs exist which indicate prognosis, course of disease and resistance or sensitivity to ongoing treatment. These biomarkers may be a basis for creation of new drugs for epigenetic

In acute myeloid leukemia (AML), some sncRNAs may play roles in oncogenes and other sncRNAs may be tumor suppressors. Oncogenic sncRNAs are miRNA-155, miRNA-17-92 cluster, miRNA-221, miRNA-21, etc. Tumor suppressive functions have miRNA-15a/16 cluster, miRNA-29b, miRNA-181b and members of let-7 cluster [28]. These sncRNAs may be deter-

Acute myeloid leukemia (AML) is a heterogeneous hematologic disease, which characterizes with disturbances of differentiation and maturation of hematopoietic stem cells or progenitor cells and appearance of immature blasts in periphery blood. Any classifications of AML are existing (WHO, 2008 with corrections in 2016) [29]. Classification of AML in dependence of genetic abnormalities is one of the basic classifications for this disease. All genetic changes in AML are also associated with imbalance of expression of different sncRNAs. These sncRNAs can be determined as biomarkers of particular type of AML. In **Table 1**, presents the most comprehensive analysis of dysregulated sncRNAs in dependence of AML type. All displayed

miRNA, which most often involved in pathologic processes in AML are let-7 family of miR-NAs, miRNA-16, 17–92 cluster, miRNA-29, miRNA-30, miRNA-146, miRNA-150, miRNA-155, miRNA-196 and miRNA-223. The oncogenic markers are miRNA-17-92 cluster, miRNA-155 and miRNA-196; the tumor suppressive are miRNA-15/16, let-7 family, miRNA-29, miRNA-

and Ago3 Slicer [22–25].

therapy of cancers.

**2. sncRNAs in AML**

**1.5. Role of sncRNAs in carcinogenesis**

mined as biomarkers and prognostic markers in AML.

**2.2. Role of separated miRNAs and piRNAs in AML**

30, miRNA-146, miRNA-150 and miRNA-223 (**Figure 1**).

**2.1. sncRNAs as biomarkers and prognostic markers of AML**

sncRNAs profiles were taken from clinical investigations in AML patients.

#### **1.3. micro-RNAs**

miRNAs are small, single-stranded RNAs (ssRNAs) that are less than 24 nucleotides in length. They control translation of more than 60% of protein-coding genes. Four different mechanisms of regulation exist: inhibition of translation initiation, suppression of translation elongation, degradation of co-translational protein and initiation of translation termination [4–8].

The biogenesis of miRNAs was previously described [9–13]. Primary miRNAs (pri-miR-NAs) are mostly transcribed by RNA Polymerase II (RNA Pol II). After that, pri-miRNAs undergo nuclear processing by the microprocessor complex of RNAse III enzyme Drosha/ DGCR8 (DiGeorge syndrome critical region gene 8), followed by export into the cytoplasm as pre-miRNAs complexed with exportin5 and RAN GTP [9–11]. In the cytoplasm, immature miRNAs are duplexes by the cytoplasmic RNase III Dicer together with its catalytic partner Trans-activator RNA (tar)-binding protein (TRBP). Dicer/TRBP cleavage pre-miRNAs in duplex RNA (dsRNA) is loaded onto Argonaute (AGO) proteins to generate the RNAinduced silencing complex (RISC). RISC contains a single-stranded miRNAs and guide them to theirs target mRNAs [12, 13].

#### **1.4. Piwi-interacting RNAs**

PiRNAs, 26–32 nt long small non-coding RNAs that are associated with the piwi-class AGO protein family, are generated independently of Dicer from single-stranded precursors [14]. The primary function of these sncRNAs is silencing of transposable elements through de novo DNA methylation [15]. Some piRNAs are silencing target protein-coding genes [16]. Recently two models of piRNA biogenesis were proposed: the primary processing and the secondary amplification (ping-pong amplification loop) pathways. In the germline, piRNA biogenesis involves both pathways. Two putative RNA helicases, Armi and FS(1)Yb (Female Sterile (1) Yb; also known as Yb) and a nuclease, Zuc (Zucchini), as factors of primary piRNA biogenesis. PiRNA precursors or intermediates obtained from uni-strand clusters are cut by Zuc to produce piRNAs that bind to piwi proteins. Amplification of loop pathway is activated by piRNA derived from primary biogenesis pathway. There should be a relative increase in abundance of complementary piRNAs due to the amplification. The primary pool of piRNAs amplifying sequences is silencing active transposons in the secondary ping-pong amplification loops cycles. The ping-pong amplification loop characterized in many animal species requires piwi subfamily proteins: piwi and Aub [17–19]. Sense-strand piRNAs react with Ago3 [20], whereas antisense piRNAs bound to Piwi or Aub [21]. In the ping-pong amplification loop model of piRNA biogenesis, antisense piRNAs in complex with Aub directly cleaves sense-strand transposon sequences, generating sense piRNAs for Ago3. The Ago3-piRNA complex then directs cleavage of antisense piRNA precursors, generating antisense piRNAs for Aub. The 5′-ends of amplified secondary piRNAs are determined by Aub and Ago3 Slicer [22–25].

#### **1.5. Role of sncRNAs in carcinogenesis**

sncRNAs may play double-faced roles in carcinogenesis as oncogenes and tumor suppressors. As oncogenes sncRNAs function in tumor initiation, progression and resistance to therapies; as tumor suppressors, sncRNAs inhibit cell growth, induce apoptosis, block cell cycle and promote cell differentiation [26, 27]. In every pathologic condition, its own biomarker sncRNAs exist which indicate prognosis, course of disease and resistance or sensitivity to ongoing treatment. These biomarkers may be a basis for creation of new drugs for epigenetic therapy of cancers.
