Role of microRNA dysregulation in childhood acute leukemias: Diagnostics, monitoring and therapeutics: A comprehensive review

Table 1 Targets of microRNA associated with acute leukemia (based on data in Human microRNA Disease Database http://www.cuilab.cn/hmdd)

miRNA name	Description	Ref.
hsa-let-7b	In patients with ALL, the expression of microRNA let-7b is regulated by methylation of CpG islands in the region of the genomic promoter. The microRNA let-7b may act as a tumor suppressor, whose low expression is involved in ALL development, indicating the microRNA let-7b may become a new therapeutic target for ALL	[154]
hsa-mir-17	Differential expression of miR-17~92 identifies BCL2 as a therapeutic target in BCR-ABL-positive B-lineage acute lymphoblastic leukemia	[155]
hsa-mir-99a, hsa-mir-100	miR-100 and miR-99a have critical roles in altering cellular processes by targeting both the FKBP51 and IGF1R/mTOR signaling pathways in vitro and might represent a potential novel strategy for ALL treatment	[43]
hsa-mir-101	Hsp90 co-chaperone – p23, is regulated by hsa-miR-101, which is downregulated in childhood ALL cases	[156]
hsa-mir-124	miR-124 contributes to glucocorticoid resistance in acute lymphoblastic leukemia by promoting proliferation, inhibiting apoptosis, and targeting the glucocorticoid receptor	[157]
hsa-mir-126	miR-126 plays a critical but 2-faceted role in leukemia and thereby uncovers a new layer of miRNA regulation in cancer. miR-126 depletion can sensitize AML cells to standard chemotherapy, which suggests that miR-126 represents a promising therapeutic target	[158]
hsa-mir-142	Upregulation of miR-142-3p decreased MLL-AF4 expression in the RS4;11 leukemic cell line. Ectopic expression of miR-142-3p remarkably suppressed cell proliferation and induced apoptosis, and exogenous expression of miR-142-3p strongly reduced the expression of MLL-AF4 target genes such as homeobox A HOXA9, HOXA7, and HOXA10	[159]
hsa-mir-181a	Ectopic expression of miR-181a resulted in decreased CD10 hyperexpression in ETV6/RUNX1+ primary patient samples. miR-181a could target ETV6/RUNX1 and cause a reduction in the level of that oncoprotein, cell growth arrest, an increase in apoptosis, and induction of cell differentiation in ETV6/RUNX1+ cell line	[48]
hsa-mir-181a	miR-181a play role as negative regulator for the TGF-β1 signaling pathway	[47]
hsa-mir-196b	miR-196b becomes nonfunctional in T-cell ALL as a consequence of mutations in 3'-UTR of the c-myc gene in T-cell ALL cellular models	[160]
hsa-mir-196b, hsa-mir-1290	miR196b and miR-1290 target the IGFBP3 3'-UTR and participate in the antitumor effect of resveratrol via regulation of IGFBP3 expression in acute lymphoblastic leukemia. miR-196b/miR-1290 are potential therapeutic targets for ALL	[161]
hsa-mir-221 hsa-mir-222	Overexpression of miR-221 in ALL cells prompted cell-cycle progression and sensitization of ALL cells to cytotoxic agents. Niche-influenced miR-221/222 may define a novel therapeutic target in ALL	[162]
hsa-mir-520 h	POLD1 and MCM2 were found to be regulated by miR-520H via E2F1. High expression of POLD1, MCM2, and PLK4 might play positive roles in the recurrence of ALL	[163]
hsa-mir-595	miR-595 suppresses the cellular uptake and cytotoxic effects of methotrexate by targeting SLC19A1 in CEM/C1 cells	[164]
hsa-mir-664	miR-664 negatively regulates PLP2 and promotes cell proliferation and invasion in T-cell acute lymphoblastic leukemia. miR-664 may represent a potential therapeutic target for T-ALL intervention	[115]
hsa-mir-708	The expression level of miR-708 reflects differences among the clinical types of common-ALL, and CNTFR, NNAT, and GNG12 were identified as targets of miR-708	[165]
hsa-mir-2909	The miR-2909-KLF4 molecular axis is able to differentiate between the pathogeneses of pediatric B- and T-cell ALLs, which may represent a new diagnostic/prognostic marker	[166]

MiRNA: MicroRNA; ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; Hsp90: Heat shock protein 90; TGF-β1: Transforming growth factor beta 1; UTR, Untranslated region; POLD1: Polymerase delta 1; MCM2: Minichromosome maintenance complex component 2; PLK-4: Polo-like kinase 4.

Table 2 MicroRNAs associated with resistance to commonly used drugs in childhood acute leukemia treatment

Drug name	Most discriminating microRNAs
Prednisolone	miR-99a, miR-125a, mir-128b, miR-210, miR-221, miR-550, miR-595, miR-633, miR-638, miR-652
L-asparaginase	miR-210, miR-454
Vincristine	miR-9, miR-99a, miR-100, miR-124, miR-125b, miR-126, miR-128b, miR-141, miR-200c, miR-218, miR-625, miR-633, miR-629, miR-1206
Prednisone	miR-15a, miR-18a, miR-16-1, miR-128b, miR-193a, miR-218, miR-223, miR-532, miR-550, miR-625, miR-633, miR-638
Daunorubicin	miR-99a, miR-100, miR-125b, miR-126, miR-199b, miR-203, miR-210, miR-335, miR-383, let-7c
Doxorubicin	miR-125b
Methotrexate	miR-595, miR-1206, miR-6083
Cytarabin	miR-562
Dexamethasone	miR-210
Imatinib	miR-203
Staurosporine	miR-125b