Select recurrent genetic lesions in childhood AML
| Genetic lesion . | Incidence in pediatric AML, % . | Outcome . | Potential therapeutic implications . | Comments . |
|---|---|---|---|---|
| Recurrent structural chromosomal aberrations | ||||
| t(15;17)(q22;q12) and other rare variants; PML-RARA or other RARA fusion; rare RARB and RARG fusions | ∼5 | Favorable | ATRA; arsenic | Acute promyelocytic leukemia; associated with life-threatening coagulopathy; differentiation syndrome with ATRA |
| t(8;21)(q22;q22); RUNX1-RUNX1T1 | ∼15 | Favorable | Dasatinib (targeting KIT kinase) | Associated with mutations of activated signaling, most commonly KIT and NRAS/KRAS; associated with -X/-Y, mutations of chromatin modifiers and cohesin complex members |
| Inv(16)/t(16;16)(p13.1;q22); CBFβ-MYH11 | 10-15 | Dasatinib (targeting KIT kinase) | Often M4Eo morphology; associated with mutations of activated signaling, most commonly KIT and NRAS/KRAS | |
| t(11;v)(q23;v);t(v;11)(v;q23); KMT2A rearrangements; KMT2A-AF9 most common | 10-15 children and adolescents; 35-50 infants | Overall neutral but fusion-specific impact on prognosis | Hypomethylating agents; DOT1L inhibitors; menin-KMT2A protein-protein interaction inhibitors; PRMT5 inhibitors; LSD1 inhibitors | Also common in topo II inhibitor–associated t-AML |
| Monosomy 7, del(7q) | 1-3 | Unfavorable | Del(7q) is relatively common in CBF AML but is not associated with worse outcome | |
| Monosomy 5, del(5q) | 1-2 | Unfavorable | ||
| 11q15 cryptic translocations; NUP98 fusions most commonly NUP98-NSD1 | 4-5 | Possibly unfavorable; combined FLT3-ITD and NUP98-NSD1 fusion associated with poor prognosis | Most common in children 3-14 y; associated with FLT3-ITD and WT1 mutations; HOX overexpression; NUP98-KDM5A common in AMKL, where it is highly associated with mono- and biallelic RB1 deletion | |
| t(1;22)(p13;q13); RBM15-MKL1 fusion | ∼10 of AMKL | Intermediate | ||
| Inv(16)(p13.3q24.3); CBFA2T3-GLS2 fusion | 15-20 AMKL | Unfavorable | GLI inhibitors (GANT61) | |
| HOX gene fusions | ∼15 AMKL | Intermediate | Associated with CTCF/Cohesin, MPL, and activated signaling pathway lesions | |
| Common molecular lesions | ||||
| FLT3-ITD mutations | 15-20 | High–allelic ratio FLT3-ITD mutation associated with poor outcome; FLT3-ITD plus NPM1 mutations favorable; FLT3-ITD plus WT1 or NUP98-NSD1 unfavorable | FLT3-targeting TKIs (eg, sorafenib, quizartinib, midostaurin) | Associated with NPM1 and WT1 mutations and NUP98-NSD1 fusion |
| Other FLT3 mutations | 10-15 | Possibly poor outcome | Non-D835Y mutations may be sensitive to FLT3-targeting TKIs | |
| NPM1 mutations | ∼10 | Favorable | DOT1L inhibitors; menin-KMT2A inhibitors | Exceedingly rare in children <3 y, increased incidence with age; associated with FLT3-ITD mutations; trilineage dysplasia in 25% |
| CEBPA mutations | 5-10 | Favorable | More common in adolescents; associated with normal karyotype | |
| Ras pathway mutations | 40-50 | Neutral | MEK inhibitors; PI3K inhibitors | Highly prevalent in infant AML, decreased incidence with age; associated with CBF AML |
| KIT mutations | 10-15; 20-25 of CBF AML | Possibly worse outcome for CBF patients with KIT mutations | Dasatinib | |
| WT1 mutations | 15 | Neutral but combination of FLT3-ITD and WT1 mutation associated with poor prognosis | Associated with FLT3-ITD mutations |
| Genetic lesion . | Incidence in pediatric AML, % . | Outcome . | Potential therapeutic implications . | Comments . |
|---|---|---|---|---|
| Recurrent structural chromosomal aberrations | ||||
| t(15;17)(q22;q12) and other rare variants; PML-RARA or other RARA fusion; rare RARB and RARG fusions | ∼5 | Favorable | ATRA; arsenic | Acute promyelocytic leukemia; associated with life-threatening coagulopathy; differentiation syndrome with ATRA |
| t(8;21)(q22;q22); RUNX1-RUNX1T1 | ∼15 | Favorable | Dasatinib (targeting KIT kinase) | Associated with mutations of activated signaling, most commonly KIT and NRAS/KRAS; associated with -X/-Y, mutations of chromatin modifiers and cohesin complex members |
| Inv(16)/t(16;16)(p13.1;q22); CBFβ-MYH11 | 10-15 | Dasatinib (targeting KIT kinase) | Often M4Eo morphology; associated with mutations of activated signaling, most commonly KIT and NRAS/KRAS | |
| t(11;v)(q23;v);t(v;11)(v;q23); KMT2A rearrangements; KMT2A-AF9 most common | 10-15 children and adolescents; 35-50 infants | Overall neutral but fusion-specific impact on prognosis | Hypomethylating agents; DOT1L inhibitors; menin-KMT2A protein-protein interaction inhibitors; PRMT5 inhibitors; LSD1 inhibitors | Also common in topo II inhibitor–associated t-AML |
| Monosomy 7, del(7q) | 1-3 | Unfavorable | Del(7q) is relatively common in CBF AML but is not associated with worse outcome | |
| Monosomy 5, del(5q) | 1-2 | Unfavorable | ||
| 11q15 cryptic translocations; NUP98 fusions most commonly NUP98-NSD1 | 4-5 | Possibly unfavorable; combined FLT3-ITD and NUP98-NSD1 fusion associated with poor prognosis | Most common in children 3-14 y; associated with FLT3-ITD and WT1 mutations; HOX overexpression; NUP98-KDM5A common in AMKL, where it is highly associated with mono- and biallelic RB1 deletion | |
| t(1;22)(p13;q13); RBM15-MKL1 fusion | ∼10 of AMKL | Intermediate | ||
| Inv(16)(p13.3q24.3); CBFA2T3-GLS2 fusion | 15-20 AMKL | Unfavorable | GLI inhibitors (GANT61) | |
| HOX gene fusions | ∼15 AMKL | Intermediate | Associated with CTCF/Cohesin, MPL, and activated signaling pathway lesions | |
| Common molecular lesions | ||||
| FLT3-ITD mutations | 15-20 | High–allelic ratio FLT3-ITD mutation associated with poor outcome; FLT3-ITD plus NPM1 mutations favorable; FLT3-ITD plus WT1 or NUP98-NSD1 unfavorable | FLT3-targeting TKIs (eg, sorafenib, quizartinib, midostaurin) | Associated with NPM1 and WT1 mutations and NUP98-NSD1 fusion |
| Other FLT3 mutations | 10-15 | Possibly poor outcome | Non-D835Y mutations may be sensitive to FLT3-targeting TKIs | |
| NPM1 mutations | ∼10 | Favorable | DOT1L inhibitors; menin-KMT2A inhibitors | Exceedingly rare in children <3 y, increased incidence with age; associated with FLT3-ITD mutations; trilineage dysplasia in 25% |
| CEBPA mutations | 5-10 | Favorable | More common in adolescents; associated with normal karyotype | |
| Ras pathway mutations | 40-50 | Neutral | MEK inhibitors; PI3K inhibitors | Highly prevalent in infant AML, decreased incidence with age; associated with CBF AML |
| KIT mutations | 10-15; 20-25 of CBF AML | Possibly worse outcome for CBF patients with KIT mutations | Dasatinib | |
| WT1 mutations | 15 | Neutral but combination of FLT3-ITD and WT1 mutation associated with poor prognosis | Associated with FLT3-ITD mutations |
AMKL, acute megakaryoblastic leukemia; ATRA, all-trans-retinoic acid; CBF, core binding factor; ITD, internal tandem duplication; M4Eo, monocytic acute myeloid leukemia with eosinophilia; NUP98, nucleoporin 98-kDa; RARA, retinoic acid receptor α; RARB, retinoic acid receptor β; RARG, retinoic acid receptor γ; TKI, tyrosine kinase inhibitor.