The functional role of microRNA in acute lymphoblastic leukemia: relevance for diagnosis, differential diagnosis, prognosis, and therapy

Figures & data

Figure 1 Biogenesis of miRNA.

Abbreviations: miRNA, MicroRNA; mRNA, messenger RNA; RNA pol II, RNA polymerase II; Pri-miRNA, primary miRNA; Pre-miRNA, precursor miRNA; RISC, RNA induced silencing complex.

Figure 2 The functional mechanism of miRNA.

Abbreviations: mRNA, messenger RNA; miRNA, microRNA; RISC, RNA-induced silencing complex.

Figure 3 miRNAs relevant to normal lymphopoiesis.

Notes: Green text indicates microRNAs that are underexpressed, red text indicates microRNAs that are overexpressed, and black text indicates microRNAs that are unclear. Where miRNA is shown next to the cell, it indicates miRNA expression level at the cell stage. Where miRNA is shown below or above arrows, it indicates a level of the miRNA is needed for the cells to differentiate to next stage.
Abbreviations: miR, miRNA; miRNA, microRNA; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; DN, double-negative; DP, double-positive; HSC, hematopoietic stem cell; Th1, T-helper 1 cell; Th2, T-helper 2 cell; Th17, T-helper 17 cell; Treg, regulatory T-cell; pro-B, progenitor B-cell; pre-B, precursor B-cell.

Table 1 The documented information of miRNAs in diagnosis and differential diagnosis of ALL

miRNA	Gene locus		Target	Main effect of the target in hematopoiesis or oncogenesis	Value in diagnosis or differential diagnosis of ALL
miRNA-223	Xq12		FOXO^Citation103	FOXO represses tumor suppression genes, such as BIM,	Higher expression in the subset of adult T-cell ALL displaying myeloid features than the other subsets;^Citation66 downregulated in ALL compared with AML^Citation73,Citation74
			LMO2^Citation104	Trail, and Fas L, which induce apoptosis;^Citation103 LMO2 is a pro-oncogene in T-cells^Citation105,Citation106
Let-7b	22q13		HMGA^Citation107	HMGA is oncogenic	Downregulated in ALL compared with AML^Citation73,Citation74
miRNA-128a	2q21		BMI-1^Citation108	A gene regulates self-renewal of leukemic cells^Citation109	Upregulated in ALL compared with AML;^Citation73,Citation74 highly expressed in E2A/PBX1-positive cases^Citation60
miRNA-196a	17q21-22		HOXB8^Citation110 ERG^Citation111	HOXB8 and ERG increase cell survival and proliferation of progenitors^Citation110	Downregulated in T-ALL compared with AML; high miRNA-196a expression is significantly associated with an early immunophenotype of T-ALL^Citation110
miRNA-196b	7p15, between HOXA9 and HOXA10^Citation110	c-myc^Citation101 ERG^Citation111		ERG and c-myc increase cell survival and proliferation of progenitors^Citation112	Downregulated in B-cell ALL;^Citation113 upregulated in MLL-rearranged^Citation63 and other HOXA-activated ALLs^Citation114
miRNA-125b-1	11q24		May be Trp53inp1^Citation115	Trp53inp1 is a proapoptotic gene^Citation116	Upregulated in B-ALL with chromosomal translocation t(11; 14) (q24; q32)^Citation115
miRNA-128-3p	Not clear		PHF6^Citation117	Might be a tumor suppressor gene^Citation118	Significantly higher expressed in ALL samples than in AML or normal samples^Citation63,Citation73
miRNA-148a	7p15.2		BIM, PTEN^Citation119	BIM and PTEN are proapoptotic genes^Citation119	Highly expressed in T-ALL cases^Citation60
miRNA-151	Chromosome: 8		ITK, ZAP-70^Citation60	ITK plays an important role in normal T-cell functions and in the pathophysiology of both autoimmune diseases and T-cell malignancies;^Citation120 ZAP-70 expression is associated with the E2A/PBX1 rearrangement^Citation121	Downmodulated in T-ALL^Citation60
miRNA-424	Xq26.3		NFI-A,^Citation122 VEGFR2^Citation123	NFI-A modulates the differentiation of hematopoietic progenitors;^Citation124 VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex^Citation125	Highly expressed in patients with T-ALL and down modulated in AMLs with NPM1mutA^Citation60,Citation122
miRNA-23a	19p13.13		HOXB4^Citation126 BCR/ABL^Citation127 CXCL12^Citation128	HOXB4 is oncogenic;^Citation126 BCR/ABL is oncogenic;^Citation127 CXCL12 regulates the interaction between hematopoietic stem and progenitor cells and BM stromal cells^Citation128	Higher expressed in AML compared with ALL^Citation72,Citation129
miRNA-27a	19p13.13		4-3-3θ^Citation130	4-3-3θ is antiapoptotic^Citation130	Higher expressed in AML compared with ALL;^Citation72 downregulated in ALL compared with hematopoietic stem-progenitor cells^Citation130
miRNA-221	Xp11.3		p27^Citation131	p27 prevent cell-cycle progression from G1 to S phase^Citation131	Higher expressed in AML compared with ALL^Citation72,Citation132

Abbreviations: miRNA, microRNAs; ALL, acute lymphoblastic leukemia; AML, acute myeloblastic leukemia; BM, bone marrow.

Figure 4 The mechanism between miRNA-196b and their targets.

Notes: 1*, chromosomal rearrangements lead to overexpression of ERG; 2*, mutation in the 3′UTR of C-myc leads to the lost ability of down regulation of miRNA-196b in T-ALL; ETS gene is a oncogene; AATF gene is anti-apoptotic; Bcl-2 gene represses the mitochondrial apoptosis signals; hTERT gene encodes telomerase catalytic submit related to immortalization and carcinogenesis; BIM gene is pro-apoptotic. Data from Bhatia et al¹⁰¹ and Loughran et al.¹⁰²
Abbreviations: miR, miRNA; miRNA, microRNA; mRNA, messenger RNA; RISC, UTR, untranslated region; ALL, acute lymphoblastic leukemia.

Table 2 Other documented information of miRNAs for prognosis and/or treatment of ALL

miRNA	Gene locus	Target	ALL type	Value for prognosis or therapy
miRNA-210	11p15.5	May be SAR1B or HINT1^Citation133	Not mentioned	Lower expression level in patients prone to relapse and insensitive to chemotherapeutic drug than in other patients (P<0.001)^Citation133
miRNA-124a	8p23	CDK6, Rb^Citation97	Not mentioned	Low expression was associated with higher relapse rate (P=0.001) and mortality rate (P<0.001)^Citation97
miRNA-152	17q21	DNMT1^Citation89,Citation134	MLL rearranged: t(4;11)-positive	Low expression was strongly correlated with a poor clinical outcome^Citation89
miRNA-664	Chromosome 1	PLP2^Citation135	T-ALL	Inhibition of miR-664 may be a potential therapeutic strategy for the treatment of T-ALL^Citation135
miRNA-100/99a	11q24 and 21q21, respectively	FKBP51 and IGF1R/mTOR^Citation136	Not mentioned	Expression levels were related to the patient’s 5-year survival;^Citation136 approximately 20-fold upregulation predicted resistance to vincristine and daunorubicin^Citation64
miRNA-708	11q14	CNTFR, NNAT, and GNG12^Citation137	B-ALL	Low expression of miR-708 was correlated with resistance to GCs in pediatric B-ALL^Citation138
miRNA-193b-3p	Not found	MYB^Citation139	T-ALL	An entry point for efficient MYB targeting-oriented therapies for human T-ALL^Citation139
miRNA-27a	19p13.13	Bax, Bad, and 14-3-3θ^Citation130	Not mentioned	May be a potential therapeutic target^Citation130

Abbreviations: miRNA, microRNAs; ALL, acute lymphoblastic leukemia; GCs, glucocorticoids.

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