**7. miRNAs as therapeutic targets in acute lymphoblastic leukemia**

Nowadays, advances in our understanding of the molecular carcinogenesis of the human cancers and the extensive research on generate and implement new combined and targeted therapies, and have allowed to know specific molecular therapeutic targets. However, there is still a continuous need for development of new therapeutic tools for applicability.

RNA molecules actually are the therapeutic targets promising in the molecular oncology. The ability of miRNAs to regulate important cellular processes, by concurrently regulating multiple targets, their inherent role in carcinogenesis as oncogenes or tumor suppressor genes, and the aberrant dysregulation of their

*Advances in Hematologic Malignancies*

independent of p53 [50].

prognosis [61].

longer over survival [64].

role for miR-125b in early hematopoiesis [46].

cells ectopically expressing miR-125b that showed an increase in white blood cell count, in particular in neutrophils and monocytes, associated with a macrocytic anemia. These mice developed B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, or a myeloproliferative neoplasm, suggesting an important

Patients group with high miR-21 expression was significantly associated with those aged <2 and > 10 years, lower platelets count, more incidence of central nervous system (CNS) infiltration, and poorer treatment outcome also; patients with high miR-21 showed a significantly poorer disease-free survival (DFS) and overall survival (OS) compared with those with low miR-21 expression group [47]. Also, miR-92a expression is significantly higher in ALL compared with peripheral blood mononuclear cells (PBMNCs) from healthy volunteers. Likewise, the expression levels of miR-99a, miR-100, and miR-128b correlated high-risk prognostic factors, including white blood cell (WBC) count, ALL subclassification (T-cell and B-cell ALL), the MLL-rearranged gene, and the BCR-ABL fusion gene, suggesting possible relation of miR-99a, miR-100, and miR-218b with prognosis [48, 49]. It has also been reported that mir-125b-2 is highly expressed in childhood ETV6/RUNX1 (TEL/AML1) leukemias and confers survival advantage to growth inhibitory signals

More specifically, miR-9, miR-24, and miR-92a expression was significantly increased in a subset of ALL cells, and ALL patients with overexpressed miR-24 and miR-92a had poor prognoses [51–53]. Wang et al. (2010) observed that miR-146a, miR-181a/c, and miR-221 were significantly associated with overall survival of the ALL patients. Expression level of miR-146a and miR-181a/c was associated with a poor outcome (i.e., poor prognosis/short-term survival), whereas that of miR-221 was associated with a good outcome (i.e., good prognosis/long-term survival) [54], while that of miR-423-5p is associated with a poorer survival in patients with ALL [55]. Otherwise, the reduced expression of miR-155, miR-181b, miR-182, miR-143, miR-210, and miR-335 is associated with poor outcome of pediatric ALL [56–60]. Also, the expression of miRNAs miR-18a, miR-532, miR-218, miR-625, miR-193a, miR-638, miR-550, and miR-633 is associated with early relapse in childhood ALL, suggesting possible relation of these miRNAs with

The high miR-16 expression is associated with hyperleukocytosis and poor cytogenetic groups. In B-cell ALL patients, the DFS was significantly shorter in patients with high miR-16 levels. While in T-cell ALL patients, for both DFS and overall survival, a significant trend was found with a survival shortening from the lowest to the highest miR-16 levels [62, 63]. Likewise, it was reported that the expression of miR-16 was upregulated in cases of T lymphoblastic lymphoma/leukemia (T-LBL/ ALL), and the high expression group of miR-16 was significantly correlated with

For instance, Gimenes-Teixeira et al. reported that T-ALL patients with high miR-221 expression had significantly lower 5-year overall survival (OS) rates compared with those with low miR-221 expression [65]. Oliveira et al. observed that lower levels of miR-29a were significantly associated with higher blast counts in the bone marrow and with increased disease-free survival in T-ALL patients [66].

**6. miRNAs in response to commonly used chemotherapy agents in** 

Despite the great effort of current treatment strategies, drug resistance still remains a major cause of chemotherapy failure and relapse in pediatric patients.

**pediatric acute lymphoblastic leukemia**

**62**

expression levels in cancer, can represent a viable therapeutic strategy and a powerful intervention tool in **leukemia** [73]. For example, in leukemia cells isolated from individuals with BCR/ABL, TKI-resistant Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph + ALL) was observed an increase in levels of DNMT3A in association with downregulation of miR-217; these observations are clinically relevant; and inhibition of DNMT3A by forced expression of miRNA-217 may benefit in preventing drug resistance to TKI treatment in Philadelphiachromosome-positive ALL patients [74]. Another therapeutic strategy for BCR-ABL-positive ALL is miRNA-203, which has as direct target to BCR-ABL1 and ABL1, proteins with activity tyrosine kinase. This miRNA is silenced by genetic and epigenetic mechanisms in hematopoietic malignancies expressing either ABL1 or BCR-ABL1. However, the restoration of the miRNA-203 expression reduces ABL1 and BCR-ABL1 levels and inhibits cell proliferation [75]. miRNA-143 was identified as a regulator of MLL-AF4 expression and is epigenetically repressed by promoter hypermethylation in MLL-AF4-positive primary blasts and cell lines;upregulation of miRNA-143 expression by demethylation has therapeutic promise for MLL-AF4 B-cell ALL [76].

It is also important to consider that some miRNAs can behave as oncogenes in one cancer type and as tumor suppressive genes in others. It has been reported that miR-221 maintains a high expression in hepatic cancer and exerts an oncogenic function by targeting tumor suppressor PTEN, but this miRNA acts as a tumor suppressor in erythroblastic leukemia by inhibiting the KIT oncogene expression [77, 78]. Thus, identification of specific biological functions, type of cancer, and targets of miRNAs is a basic aspect when considering miRNA therapeutics.

## **8. Summary and future directions**

Various studies have demonstrated that the oncomiRs or tumor suppressor miRNAs expression may significantly have potential how diagnostic and/ or prognostic biomarkers, as well as monitoring the disease progression and in the response to treatment, and it may be a therapeutic target for treatment in ALL. Also, miRNAs expression levels may play an important role in the genesis and evolution of the ALL. Nevertheless, the biological effects and relevant target genes of many miRNAs that are deregulated and/or prognostically relevant in ALL need to be identified and characterized. Therefore, novel anti-ALL agents are needed to overcome chemotherapy resistance and reduce cytotoxicity. The mimics- and/or anti-miRNAs may be a good alternative. However, more experiments are required to evaluate the feasibility and safety of mimics- and/or anti-miRNAs in the clinical treatment.

### **Acknowledgements**

This work was supported by the Universidad Autónoma de Guerrero. Yazmín Gómez-Gómez (CVU: 236728) and Jorge Organista-Nava (CVU: 236745) were recipient of postdoctoral fellowships from CONACYT.

**65**

**Author details**

Yazmín Gómez-Gómez†

and Marco Antonio Leyva-Vázquez\*

provided the original work is properly cited.

† These authors contributed equally to this work

© 2019 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,

\*Address all correspondence to: leyvamarco13@gmail.com and joorna@gmail.com

, Jorge Organista-Nava\*†

Molecular Biomedicine Laboratory, School of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo, Guerrero, Mexico

, Berenice Illades-Aguiar

*miRNAs in Acute Lymphoblastic Leukemia: Diagnosis, Prognosis and Target Therapeutic*

*DOI: http://dx.doi.org/10.5772/intechopen.84318*

## **Conflict of interest**

The authors declare that there are no conflicts of interest.

*miRNAs in Acute Lymphoblastic Leukemia: Diagnosis, Prognosis and Target Therapeutic DOI: http://dx.doi.org/10.5772/intechopen.84318*
