**6. miRNAs in response to commonly used chemotherapy agents in pediatric acute lymphoblastic leukemia**

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

**63**

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

miRNAs have not only become tools for classifying subtypes of ALL and in support of the prognosis of this disease, but also studies have reported the classification of patients sensitive or resistant to drugs based on the expression of

Glucocorticoids (GCs) regulate proliferation, differentiation, metabolism, and cell survival in many tissues. In lymphocytes, they affect cell cycle progression, influence immunoglobulin and lymphokine production, and induce apoptosis in immature lymphoblasts [67]. Actually, these drugs are used clinically in the treatment of childhood acute lymphoblastic leukemia (ALL) and other lymphoid malignancies. In the group of glucocorticoids that is administered to patients with ALL is the prednisone; unfortunately, a proportion of patients are insensitive to this drug. A study in 49 ALL patients showed that miR-18a, miR-532, miR-218, miR-625, miR-193a, miR-638, miR-550, and miR-633 could distinguish prednisone-sensitive patients from prednisone-insensitive patients [68]. In contrast, other authors in a group of 81 children with newly diagnosed ALL, no discriminative microRNAs were

It is well known that the presence of translocations in ALL is a frequent and prognostic influence event. In leukemia, MLL rearrangements are a common genetic alteration; MLL-AF4 acute lymphocytic leukemia (ALL), resulting from a balanced translocation between *MLL* and *AF4,* occurs in approximately 50% of ALL cases in infants, 2% in children, and 5–6% in adults. The poor prognosis of MLL-AF4 ALL to glucocorticoid-induced apoptosis is associated with its resistance to this drug [70]. miR-128b and miR-221 are commonly downregulated in MLL-rearranged ALL compared with other types of ALL; also these miRNAs downregulate mRNAs encoding CDKN1B, MLL, AF4, and both MLL-AF4 and AF4-MLL fusion genes that are thought to contribute to leukemia development [71]. Interestingly, the restoration of miRNA-128b downregulates target genes including *MLL*, *AF4*, and both *MLL-AF4* and *AF4-MLL* fusion oncogenes, and the restoration of miRNA-221 downregulates CDKN1B cooperatively. Thus, the sensitivity of MLL-AF4 ALL cells to GCs is strengthened [71]. Study developed by Kotani et al. supports the idea that restoration of miRNA-128b improves the sensitivity of MLL-AF4 ALL cells to GCs. This author mentioned that one novel mutation of miRNA-128b significantly reduced its processing, and the resultant downregulation of mature miRNA-128b gave rise to GCs resistance due to the failure to downregulate the fusion oncogenes [72]. This suggests that miRNA-128b and miRNA-221

Other microRNAs related with drug resistance in pediatric acute lymphoblastic leukemia are miR-454, which present a low expression in L-asparaginase-resistant cases, whereas miR-125b, miR-99a, and miR-100 show an upregulation of their

expression in patients resistant to vincristine and daunorubicin [69].

**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

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

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

found for prednisolone response [69].

could be GC (dexamethasone) sensitizers potential.

new therapeutic tools for applicability.

miRNAs.

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

miRNAs have not only become tools for classifying subtypes of ALL and in support of the prognosis of this disease, but also studies have reported the classification of patients sensitive or resistant to drugs based on the expression of miRNAs.

Glucocorticoids (GCs) regulate proliferation, differentiation, metabolism, and cell survival in many tissues. In lymphocytes, they affect cell cycle progression, influence immunoglobulin and lymphokine production, and induce apoptosis in immature lymphoblasts [67]. Actually, these drugs are used clinically in the treatment of childhood acute lymphoblastic leukemia (ALL) and other lymphoid malignancies. In the group of glucocorticoids that is administered to patients with ALL is the prednisone; unfortunately, a proportion of patients are insensitive to this drug. A study in 49 ALL patients showed that miR-18a, miR-532, miR-218, miR-625, miR-193a, miR-638, miR-550, and miR-633 could distinguish prednisone-sensitive patients from prednisone-insensitive patients [68]. In contrast, other authors in a group of 81 children with newly diagnosed ALL, no discriminative microRNAs were found for prednisolone response [69].

It is well known that the presence of translocations in ALL is a frequent and prognostic influence event. In leukemia, MLL rearrangements are a common genetic alteration; MLL-AF4 acute lymphocytic leukemia (ALL), resulting from a balanced translocation between *MLL* and *AF4,* occurs in approximately 50% of ALL cases in infants, 2% in children, and 5–6% in adults. The poor prognosis of MLL-AF4 ALL to glucocorticoid-induced apoptosis is associated with its resistance to this drug [70]. miR-128b and miR-221 are commonly downregulated in MLL-rearranged ALL compared with other types of ALL; also these miRNAs downregulate mRNAs encoding CDKN1B, MLL, AF4, and both MLL-AF4 and AF4-MLL fusion genes that are thought to contribute to leukemia development [71]. Interestingly, the restoration of miRNA-128b downregulates target genes including *MLL*, *AF4*, and both *MLL-AF4* and *AF4-MLL* fusion oncogenes, and the restoration of miRNA-221 downregulates CDKN1B cooperatively. Thus, the sensitivity of MLL-AF4 ALL cells to GCs is strengthened [71]. Study developed by Kotani et al. supports the idea that restoration of miRNA-128b improves the sensitivity of MLL-AF4 ALL cells to GCs. This author mentioned that one novel mutation of miRNA-128b significantly reduced its processing, and the resultant downregulation of mature miRNA-128b gave rise to GCs resistance due to the failure to downregulate the fusion oncogenes [72]. This suggests that miRNA-128b and miRNA-221 could be GC (dexamethasone) sensitizers potential.

Other microRNAs related with drug resistance in pediatric acute lymphoblastic leukemia are miR-454, which present a low expression in L-asparaginase-resistant cases, whereas miR-125b, miR-99a, and miR-100 show an upregulation of their expression in patients resistant to vincristine and daunorubicin [69].
