Role of microRNAs, circRNAs and long noncoding RNAs in acute myeloid leukemia

Liu, Yan; Cheng, Zhiheng; Pang, Yifan; Cui, Longzhen; Qian, Tingting; Quan, Liang; Zhao, Hongyou; Shi, Jinlong; Ke, Xiaoyan; Fu, Lin

doi:10.1186/s13045-019-0734-5

Journal of Hematology & Oncology

Table 1 miRNAs in acute myeloid leukemia

From: Role of microRNAs, circRNAs and long noncoding RNAs in acute myeloid leukemia

miRNAs	Genetic abnormalities	Altered expression	Targets	Function	Reference
miR-9	t(8;21)(q22;q22.1) RUNX1-RUNX1T1; mutated NPM1; biallelic mutations of CEBPA	↑in MLL-rearranged AML	RHOH RYBP	miR-9 was upregulated by MLL-AF9 and increased MLL-AF9-mediated cell transformation in murine hematopoietic progenitor cells in vitro and in vivo. Mice transplanted with BM progenitors that overexpressed both MLL-AF9 and miR-9 (MLL-AF9+ miR-9) had higher frequency of c-Kit+ blast cells in the BM, spleen, and peripheral blood than MLL-AF9 mice. Moreover, MLL-AF9+ miR-9 leukemic cells had a higher frequency of immature blasts	[11]
		↓in t(8;21) AML	HMGA2 LIN28B	Increase proliferation and decrease monocytic differentiation	[12]
		↓in RUNX1-RUNX1T1(+)AML	RUNX1, RUNX1T1, RUNX1-RUNX1T1	RUNX1-RUNX1T1 triggered the heterochromic silencing of miR-9-1, resulting in hypermethylation of the miR-9-1 promoter in t(8; 21) AML. Silencing of miR-9-1 promoted expression of target genes(RUNX1, RUNX1T1, and RUNX1-RUNX1T1), which inhibited differentiation and promoted the proliferation of t(8; 21) AML cell lines	[13]
		↑3YPERLINK \lline	ERG	ERG is a direct target of miR-9 which contributed to miR-9/9*-induced differentiation of progenitor cells towards neutrophils	[33]
		↑3YPERLINK \l "_ENREF_33" \o "Nowek K, 2016 #298" hor><Yeaparients with normal karyotype	Hes1	miR-9 negatively regulated Hes1 expression and knockdown of miR-9 suppressed the proliferation of AML cells by the induction of G0 arrest and apoptosis in vitro, decreased circulating leukemic cell counts in peripheral blood and bone marrow, attenuated splenomegaly, and prolonged survival in a xenotransplant mouse model	[34]
		↓in AE-positive cell lines	SIRT1	Knockdown of SIRT1 expression inhibits cell proliferation in AE-positive AML cell lines	[87]
		↓in EVI1-induced AML	FOXO1 FOXO3	Increase proliferation and decrease monocytic differentiation	[88]
miR-21	Mutated NPM1; mutated RUNX1	↑in K562/DNR	PTEN	Decreased cell sensitivity to daunorubicin	[42]
miR-21	Mutated NPM1; mutated RUNX1	↑in SKM-1 cell	PTEN/AKT pathway	Downregulation of miR-21 expression inhibits proliferation and induces G1 arrest and apoptosis in SKM-1 cell	[89]
miR-22		↓iR-22LINK \l "	CRTC1 FLT3 MYCBP	Represses the CREB and MYC pathways	[90]
miR-29b	PML-RARA; mutated NPM1	↑in K562 cells	DNMT3A DNMT3B DNMT1	Increase DNA methylation and hypermethylation	[49]
		↓in t(8;21) AML	SP1	Upregulate KIT contributing to malignant proliferation	[54]
		↓in various subtypes of AML	AKT2 CCND2	Increase cell growth, leukemic progression in vivo	[91]
		↓in various subtypes of AML	MCL-1 CXXC6 CDK6	Increase cell growth, decrease apoptosis, leukemic progression in vivo	[92]
		↓in various subtypes of AML	SP1 DNMT3A DNMT3B	Results in global DNA hypermethylation	[93]
		↑in NK cells		Damage to NK cells development and function	[94]
miR-34a	Biallelic mutations of CEBPA	↓in CEBPA mutated AML	E2F3	Increase proliferation and decrease differentiation	[95]
		↓in de novo AML	PDL1	Immune dysregulation	[96]
		↓in CEBPA mutated AML cell lines	HMGB1	Inhibit cell apoptosis and increased autophagy	[97]
miR-34b		↓iR-34bINK \l "_ENREF_	CREB	Survival signaling pathways	[98]
miR-34c-5p		↓in LSCs	RAB27B	Increase miR-34c-5p expression induced LSCs senescence ex vivo
miR-99a	Mutated RUNX1; inv(16)(p13.1q22) or t(16;16) (p13.1;q22)			High miR-99a expression could predict worse outcome in AML patients undergoing allo-HCST	[80]
		↑in initial diagnosis and relapse		Regulate self-renewal, inhibiting differentiation and cell cycle entry	[99]
		↑in AML-AF9	SMARCA5 HS2ST3 HOXA1	Increase proliferation, colony formation, cell survival, inhibite differentiation	[100]
		↑in pediatric-onset AML (M1–M5)	CTDSPL TRIB2	Increase proliferation, colony formation, cell survival	[101]
miR-103		↑in K562 cells	COP1	Increase drug resistance of K562 cells to ADR	[102]
miR-125b	t(8;21)(q22;q22.1) RUNX1-RUNX1T1; PML-RARA; mutated NPM1	↑in MDS and AML with t(2;11) (p21;q23)		Inhibit differentiation	[103]
		↑in AML	LIN28A	Uncontrolled generation of myeloid cells	[104]
			IRF4	Induce myeloid leukemia in mice by inducing immortality, self-renewal, and tumorigenesis in myeloid progenitors	[105]
		↑in pediatric AML	FES PU.1	Block monocytic differentiation of AML in vitro	[106]
		↑in AML cell lines	NF-κB	Inhibits human AML cells invasion, proliferation and promotes cells apoptosis	[107]
miR-126	t(8;21)(q22;q22.1) RUNX1-RUNX1T1; PML-RARA; mutated NPM1	↑in t(8;21) and inv(16) AML	PLK2	Inhibits cell apoptosis and increase cell viability	[108]
		↑in LSCs of AML		Increase leukemic growth, and survival of leukemic stem and progenitor cells in vivo	[109]
		↑in t(8;21) AML	ERRFI1 SPRED1 FZD7	Both gain and loss of function of miR-126 promotes leukemogenesis in vivo through targeting distinct gene signaling	[110]
		↑in LSC of CN-AML		Increase LSC maintenance and self-renewal	[111]
		↑in LSCs of AML	ADAM9, ILK, GOLPH3, CDK3, TOM1	Increase LSC maintenance and self-renewal, quiescence, chemotherapy resistance in vivo	[112]
		↑in AML cell lines	TRAF7	Suppresses apoptosis by downregulating TRAF7, which blocks the c-FLIP pathway	[113]
miR-135a		↓in AML	HOXA10	Overexpression of miR-135a inhibits the proliferation and cell cycle and promotes cellular apoptosis	[70]
miR-139-5p		↓iR-139-5p \l "_E	EIF4G2	Repressing the translation initiation, specifically inducing the translation of cell cycle inhibitor p27 Kip1	[114]
miR-143		↑inCD34 + HSPCs	ERK5	Increase granulocyte surface marker Ly6G and a more mature morphology toward granulocytes induces apoptosis	[115]
miR-144-3p		↑iR-144-3pnn JU, 2018 #227" e	NRF2	Antiapoptotic	[116]
miR-146a	t(8;21)(q22;q22.1)RUNX1-RUNX1T1; mutated NPM1	↓in del(5q) MDS	TIRAP TRAF6	Inappropriate activation of innate immune signaling in HSPCs and megakaryocytic abnormalities	[117]
		Knockout in del(5q)MDS/AML		Increase cell survival and proliferation of propagating cells through the TRAF6/p62/NF-κB complex	[118]
			IRAK1	miR-146a knockout mice develop myeloid and lymphoid malignancies	[119]
				miR-146a deletion leads to myeloproliferation in mice
		Knockout in del(5q) MDS/AML		Co-deletion of TIFAB and miR-146a may cooperate to induce TRAF6 signaling contributing to ineffective hematopoiesis	[120]
				miR-146a/Traf6 axis controls autoimmunity and myelopoiesis in mice	[121]
		↑in elderly AML patients	CXCR4 Smad4	Suppress the migration abilities of leukemia cells and promote cell cycle entry in leukemia cells	[122]
miR-149-5p		↑iR-149	FASLG	Targeting FASLG led to suppression on cell apoptosis	[123]
miR-150	PML-RARA	↓in various subtypes of AML	NANOG	Increase proliferation, colony, and sphere formation, increase tumor growth in vivo	[124]
		↓in various subtypes of AML	EIF4B, FOXO4, PRKCA, TET3	Increase cell growth and inhibits apoptosis in vitro and in vivo	[125]
		enriched in Molm-14 exosomes	CXCR4	Decrease migration of Ba/F3 cells and the surface expression of CXCR4	[60]
miR-150 miR-155		enriched in exosomes isolated from cultured AML cells	c-MYB	Hematopoiesis is suppressed by releasing exosomes that contain miR-150/miR155 targeting c-MYB	[59]
miR-181a		↑iR-181aNK \l "_ENREF_59"AML patients	KRAS, NRAS, and MAPK1	Targeting the RAS-MAPK-pathway	[126]
miR-182-5p	PML-RARA; Mutated NPM1; FLT3-ITD	↑in AML cell lines and patients blood sample	BCL2L12 BCL2	Promote cell proliferation, and reverse cisplatin (DDP) resistance	[40]
miR-182-5p	PML-RARA; Mutated NPM1; FLT3-ITD	↑in APL	CEBPα	Induce apoptosis	[127]
miR-192		↓in various subtype of AML	CCNT2	Increase proliferation and cell cycling, decrease differentiation	[128]
miR-193a		↓iR-AML1/ETO-positive leukemia cells	PTEN/PI3K signal pathway	AML1/ETO triggers the heterochromatic silencing of microRNA-193a (miR-193a) by binding at AML1-binding sites and recruiting chromatin-remodeling enzymes, which expands the oncogenic activity of AML-ETO, resulting in leukemogenesis	[35]
miR-193b	Biallelic mutations of CEBPA; mutated NPM1	↓mutati	CCND1,KIT, KRAS, or SOS2	Apoptosis and a G1/S-phase block	[74]
miR-196b	t(9;11)(p21.3;q23.3) MLLT3-KMT2A; mutated NPM1	↑in MLL associated AML		Increase proliferation and survival, and decrease differentiation and replating potential	[129]
miR-196b	t(9;11)(p21.3;q23.3) MLLT3-KMT2A; mutated NPM1	↑in MLL-associated AML	HOXA9 Meis1 FAS	Inhibit differentiation, promote cell proliferation, and induce leukemic progression in mice	[130]
miR-204	Mutated NPM1	↑in AML cells	BIRC6	Lead to AML cell apoptosis	[131]
miR-204	Mutated NPM1	↑in NPMC+ AML	HOXA10 Meis1		[132]
miR-221	t(8;21)(q22;q22.1) RUNX1-RUNX1T1; CBFB-MYH1; mutated NPM1	↑in AML	NCL/miR-221/NF-κB/DNMT1 network	Involve in DNA hypomethylation	[55]
miR-223	t(8;21)(q22;q22.1) RUNX1-RUNX1T1; CBFB-MYH1; PML_RARA; mutated NPM1; mutated RUNX1	↓in t(8;21) AML		Myeloid differentiation block	[133]
		↓in various subtypes of AML	E2F1	Lead to AML cell apoptosis	[134]
		↓in AML with adverse prognosis		Impair differentiation	[135]
		↓in various subtypes of AML	FBXW7	Increase cell proliferation and enhance apoptosis	[136]
miR-339-5p		↓in AML cells	SOX4	Inhibit cell proliferation of AML cells	[137]
miR-345-5p	Mutated NPM1	↓in AML cell lines	AKT1/2	Facilitate the proliferation of leukemia cells	[138]
miR-370		↓iR-370	NF1	Activation of the RAS signaling pathway	[139]
miR-375		↓in AML	miR-375-HOXB3-CDCA3/ DNMT3B pathway	Involve in DNA hypomethylation	[56]
miR-7977		↑in AML cell lines		miR-7977 in extracellular vesicles may be a critical factor that induces failure of normal hematopoiesis via poly(rC) binding protein 1 suppression	[61]
miR-26a-5p, miR-101-3p		↑in exosomes derived from MSCs in AML patients			[58]
miR-23b-5p, miR-339-3p, miR-425-5p		↓in exosomes derived from MSCs in AML patients			[58]
let-7a, miR-99b, miR-146a, miR-150, miR-155, miR-191, miR -1246		Enriched in exosomes from NSG mice serum			[57]
Let-7c		↓in AML patients with t(8;21) and inv(16)	PBX2	Promotes granulocytic differentiation	[140]

Abbreviations: HSPC hematopoietic stem and progenitor cell, LSC leukemia stem cells, MSCs bone marrow mesenchymal stromal cells, NSG NOD/SCID/IL-2rγnull, allo-HSCT allogeneic hematopoietic stem cell transplantation, PB peripheral blood, BM bone marrow

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