Selected miRNAs involved in AML pathogenesis
| miRNA . | Expression change . | Mechanism of dysregulation . | Confirmed targets . | Functional effect of expression . | References . | |
|---|---|---|---|---|---|---|
| OncomiR . | Tumor suppressor . | |||||
| miR-9 | ↑ MLL-rearranged AML, ↓ t(8;21), ↓ EVI1-induced AML | Promoter targeted by MLL-fusion proteins; EVI1 hypermethylates promoter | RHOH, RYBP, HMGA2, LIN28B, FOXO1, FOXO3 | ↑ Proliferation, ↑ survival, ↑ leukemogenesis in mice (MLL rearranged) | ↓ Proliferation, ↑ monocytic differentiation (t(8;21) and EVI1+) | 16-18 |
| miR-17-92 cluster | ↑ In LSCs in MLL-associated AML | Activated by MYC; epigenetically activated by MLL-fusion proteins; genomic amplification in MLL-rearranged AML | P21 | ↑ Proliferation, ↑ survival, ↓ differentiation, ↑ self-renewal, ↑ colony-forming capacity, ↑ leukemogenesis in mice | 19, 20 | |
| miR-22 | ↑ MDS/MDS-derived AML, ↓ de novo AML | Downregulated via TET1/GFI1/EZH2/SIN3A-mediated epigenetic repression and DNA copy-number loss; increased with loss of PU.1 | TET2, CRTC1, FLT3, MYCBP | ↑ Proliferation, ↑ survival, ↓ differentiation, ↑ self-renewal, overexpression leads to myeloid malignancy in mice (MDS/MDS-derived AML) | ↓ AML blast cell growth, ↑ differentiation, ↓ leukemic progression in mice (de novo AML) | 21-23 |
| miR-29b | ↓ Various subtypes of AML | Downregulated via loss of CEBPA; chromosome 7q deletions; MYC represses; NF-kB represses | MCL-1, CXXC6, CDK6, AKT2, CCND2, SP1, DNMT3A, DNMT3B | ↓ Cell growth, ↑ apoptosis, ↓ leukemic progression in vivo, ↓ KIT activation, prevents global DNA hypermethylation | 24-27, 56 | |
| miR-125b | ↑ t(2;11)(p21;q23) AML, ↑ MDS/MDS-derived AML, ↑ pediatric AML | Increased by t(2;11)(p21;q23) translocation | LIN28A, IRF4 | ↑ Proliferation, ↑ production of myeloid progenitors, ↑ self-renewal, overexpression leads to AML in mice | 28-32 | |
| miR-126 | ↑ t(8;21) AML, ↑ in LSCs of CN-AML | Promoter demethylated in t(8;21) AML | PLK2, ADAM9, ILK, GOLPH3, CDK3, TOM1, ERRFI1, SPRED1, FZD7 | ↑ Proliferation, ↑ survival, ↓ differentiation, ↑ colony-forming ability, ↑ LSC maintenance and self-renewal, ↓ cell cycling, ↑ quiescence, ↑ chemotherapy resistance | 8, 33-36 | |
| miR-146a | ↓ Various subtypes of AML, ↓ 5q syndrome MDS/MDS-derived AML | Deletion in del(5q) MDS/MDS-derived AML | TRAF6, IRAK1, TIRAP | ↓ Proliferation, ↓ survival, ↓ NF-kB activation, deletion leads to myeloproliferation in mice | 15, 37-41 | |
| miR-155 | ↑ CN-AML (highest in FLT3-ITD+ AML) | Targeted by STAT5 and NF-kB in FLT3-ITD+ AML; upregulated by MLL-fusion genes via MEIS1 | CEBPB, SHIP1, PU.1 | ↑ Proliferation, ↑ survival, overexpression leads to myeloproliferative neoplasm in mice, confers negative prognosis in CN-AML, no effect in MLL-AF9 mouse model of leukemia | 42-46 | |
| miR-193a | ↓ Various subtypes of AML (lowest in t(8;21) AML) | Epigenetically silenced by AML1/ETO | AML1/ETO, DNMT3A, HDAC3, KIT, CCND1, MDM2 | ↓ Cell growth, ↑ apoptosis, ↑ differentiation, ↓ cell cycling, ↓ KIT expression | 47, 48 | |
| miR-196b | ↑ MLL-associated AML | Activated by MLL-fusion proteins; co-expressed with HOXA9 in MLL-rearranged leukemia | HOXA9, MEIS1, FAS | ↑ Proliferation, ↑ survival, ↓ differentiation, ↓ replating potential, ↑ MLL-AF9–induced leukemic progression in mice | 49, 50 | |
| miR-223 | ↓ t(8;21) AML, ↓ various subtypes of AML | Targeted by transcription factors CEBPA (activates) and E2F1 (represses); epigenetically silenced by AML1/ETO | E2F1, MEF2C, FBXW7 | ↓ Proliferation, ↑ apoptosis, ↑ differentiation/granulopoiesis | 51-54 | |
| miRNA . | Expression change . | Mechanism of dysregulation . | Confirmed targets . | Functional effect of expression . | References . | |
|---|---|---|---|---|---|---|
| OncomiR . | Tumor suppressor . | |||||
| miR-9 | ↑ MLL-rearranged AML, ↓ t(8;21), ↓ EVI1-induced AML | Promoter targeted by MLL-fusion proteins; EVI1 hypermethylates promoter | RHOH, RYBP, HMGA2, LIN28B, FOXO1, FOXO3 | ↑ Proliferation, ↑ survival, ↑ leukemogenesis in mice (MLL rearranged) | ↓ Proliferation, ↑ monocytic differentiation (t(8;21) and EVI1+) | 16-18 |
| miR-17-92 cluster | ↑ In LSCs in MLL-associated AML | Activated by MYC; epigenetically activated by MLL-fusion proteins; genomic amplification in MLL-rearranged AML | P21 | ↑ Proliferation, ↑ survival, ↓ differentiation, ↑ self-renewal, ↑ colony-forming capacity, ↑ leukemogenesis in mice | 19, 20 | |
| miR-22 | ↑ MDS/MDS-derived AML, ↓ de novo AML | Downregulated via TET1/GFI1/EZH2/SIN3A-mediated epigenetic repression and DNA copy-number loss; increased with loss of PU.1 | TET2, CRTC1, FLT3, MYCBP | ↑ Proliferation, ↑ survival, ↓ differentiation, ↑ self-renewal, overexpression leads to myeloid malignancy in mice (MDS/MDS-derived AML) | ↓ AML blast cell growth, ↑ differentiation, ↓ leukemic progression in mice (de novo AML) | 21-23 |
| miR-29b | ↓ Various subtypes of AML | Downregulated via loss of CEBPA; chromosome 7q deletions; MYC represses; NF-kB represses | MCL-1, CXXC6, CDK6, AKT2, CCND2, SP1, DNMT3A, DNMT3B | ↓ Cell growth, ↑ apoptosis, ↓ leukemic progression in vivo, ↓ KIT activation, prevents global DNA hypermethylation | 24-27, 56 | |
| miR-125b | ↑ t(2;11)(p21;q23) AML, ↑ MDS/MDS-derived AML, ↑ pediatric AML | Increased by t(2;11)(p21;q23) translocation | LIN28A, IRF4 | ↑ Proliferation, ↑ production of myeloid progenitors, ↑ self-renewal, overexpression leads to AML in mice | 28-32 | |
| miR-126 | ↑ t(8;21) AML, ↑ in LSCs of CN-AML | Promoter demethylated in t(8;21) AML | PLK2, ADAM9, ILK, GOLPH3, CDK3, TOM1, ERRFI1, SPRED1, FZD7 | ↑ Proliferation, ↑ survival, ↓ differentiation, ↑ colony-forming ability, ↑ LSC maintenance and self-renewal, ↓ cell cycling, ↑ quiescence, ↑ chemotherapy resistance | 8, 33-36 | |
| miR-146a | ↓ Various subtypes of AML, ↓ 5q syndrome MDS/MDS-derived AML | Deletion in del(5q) MDS/MDS-derived AML | TRAF6, IRAK1, TIRAP | ↓ Proliferation, ↓ survival, ↓ NF-kB activation, deletion leads to myeloproliferation in mice | 15, 37-41 | |
| miR-155 | ↑ CN-AML (highest in FLT3-ITD+ AML) | Targeted by STAT5 and NF-kB in FLT3-ITD+ AML; upregulated by MLL-fusion genes via MEIS1 | CEBPB, SHIP1, PU.1 | ↑ Proliferation, ↑ survival, overexpression leads to myeloproliferative neoplasm in mice, confers negative prognosis in CN-AML, no effect in MLL-AF9 mouse model of leukemia | 42-46 | |
| miR-193a | ↓ Various subtypes of AML (lowest in t(8;21) AML) | Epigenetically silenced by AML1/ETO | AML1/ETO, DNMT3A, HDAC3, KIT, CCND1, MDM2 | ↓ Cell growth, ↑ apoptosis, ↑ differentiation, ↓ cell cycling, ↓ KIT expression | 47, 48 | |
| miR-196b | ↑ MLL-associated AML | Activated by MLL-fusion proteins; co-expressed with HOXA9 in MLL-rearranged leukemia | HOXA9, MEIS1, FAS | ↑ Proliferation, ↑ survival, ↓ differentiation, ↓ replating potential, ↑ MLL-AF9–induced leukemic progression in mice | 49, 50 | |
| miR-223 | ↓ t(8;21) AML, ↓ various subtypes of AML | Targeted by transcription factors CEBPA (activates) and E2F1 (represses); epigenetically silenced by AML1/ETO | E2F1, MEF2C, FBXW7 | ↓ Proliferation, ↑ apoptosis, ↑ differentiation/granulopoiesis | 51-54 | |
Table represents selected miRNAs involved in AML disease progression, with a focus on miRNAs with clinical evidence of dysregulation, as well as in vivo and in vitro functional evidence of role in leukemogenesis.
CN, cytogenetically normal; LSC, leukemic stem cell.