Pediatric Acute myeloid leukaemias (AMLs) with recurrent genetic abnormalities
2023-06-29 Sheng Xiao, MD , Chunxiao Yang Affiliation1.Brigham and Women's Hospital, Harvard Medical School, Boston, MA (USA)
Classification
Definition
Pediatric AML (pAML) is a heterogeneous disease with varying prognoses primarily determined by genetic changes.1,2 Several targeted agents have been utilized to treat AML with specific genetic aberrations. These include FLT3 inhibitors, menin inhibitors (for KMLT2A rearranged AML), IDH1 inhibitors, all-trans retinoic acid (ATRA) (for APML), hypomethylating agents, and BCL2 inhibitors. 3,4 The table below lists 14 subtypes of pAML with recurrent genetic abnormalities, although it is likely that this list will continue to expand as our knowledge advances.
| Pediatric Acute myeloid leukemias (AMLs) with recurrent genetic abnormalities | Genetic marker(s) |
|---|---|
| Acute promyelocytic leukemia with PML::RARA fusion | The dominant driver gene is the PML::RARA fusion resulting from chromosome translation t(15;17)(q24;q21). Additional frequently mutated genes include FLT3 and WT1.5,6 Pediatric APML can be effectively treated with all-trans retinoid acid (ATRA) alone, however, combination with chemotherapy gives better long-term results. Arsenic trioxide (ATO) is not typically used for pediatric APML. |
| AML with RUNX1::RUNX1T1 fusion | The dominant driver gene is the RUNX1::RUNX1T1 fusion resulting from chromosome translation t(8;21)(q22;q22). Additional frequently mutated genes include KIT, FLT3, KRAS, NRAS, CSF3R, EZH2, ASXL1, ASXL2, CBL, and WT1.7 This type of AML is often associated with a favorable prognosis.8 |
| AML with CBFB::MYH11 fusion | The dominant driver gene is the CBFB::MYH11 fusion resulting from chromosome inversion inv(16)(p13q22) or translocation t(16;16)(p13;q22). Additional frequently mutated genes include KIT, NRAS, CBL, FLT3, and WT1.9,10 Additional chromosome aberrations include trisomies 8 or 22. This type of AML is often associated with a favorable prognosis.8 |
| AML with KMT2A rearrangement | The dominant driver gene is the rearranged KMT2A resulting from chromosome rearrangement between 11q23 (KMT2A locus) and one of the >100 fusion partner genes.11 Additional frequently mutated genes include FLT3 and NRAS. Additional chromosome aberrations include trisomy 8.12 The prognosis of this type of AML depends on the specific fusion partner involved, although the majority of them are associated with a poor prognosis. |
| AML with MECOM rearrangement | The dominant driver gene is the rearranged MECOM resulting from chromosome 3 inversion inv(3)(q21q26) or translocation t(3;3)(q21;q26). Additional frequently mutated genes include SF3B1, U2AF1, IKZF1, KRAS, NRAS, and TP53. Additional chromosome aberrations include monosomy 7.13 This type of AML is often associated with a poor prognosis. |
| AML with DEK::NUP214 fusion | The dominant driver gene is the DEK::NUP214 fusion resulting from chromosome translation t(6;9)(p22;q34). Additional frequently mutated genes include FLT3 and KRAS. Additional chromosome aberrations include complex karyotype.14,15 This type of AML is often associated with a poor prognosis. |
| AML with ETV6 fusion | The dominant driver gene is the rearranged ETV6 resulting from chromosome rearrangement between 12p13 (ETV6 locus) and one of the fusion partner genes. Additional frequently mutated genes include NPM1, RUNX1, FLT3, KMT2A, and TP53. 16 Additional chromosome aberrations include trisomies 3 and 19.17 This type of AML is often associated with a poor prognosis. |
| AML with KAT6A::CREBBP | The dominant driver gene is the KAT6A::CREBBP fusion resulting from chromosome translation t(8;16)(p11;p13). Additional frequently mutated genes include FLT3 and KRAS. Additional chromosome aberrations include del(7q) and trisomy 8.18,19 This type of AML is associated with a standard risk of general pediatric AML. |
| AML with NUP98 fusion | The 2 most common NUP98 rearrangement are NUP98::NSD1 fusion from t(5;11)(q35;p15) and NUP98::KDM5A fusion from t(11;12)(p15;p13), both cytogenetically cryptic. Additional frequently mutated genes include FLT3, WT1, CEBPA, NBPF14, BCR, and ODF1. 20 Additional chromosome aberrations include trisomy 8. This type of AML is often associated with a poor prognosis. |
| AML (megakaryoblastic) with RBM15::MKL1 | The dominant driver gene is the RBM15::MKL1 fusion resulting from chromosome translation t(1;22)(p13;q13). Additional frequently mutated genes include MPL.21 Additional chromosome aberrations include complex hyperdiploid karyotype.This type of AML is associated with a simular risk of other AMKL without the fusion. |
| AML with FUS::ERG | The dominant driver gene is the FUS::ERG fusion resulting from chromosome translocation t(16;21)(p11;q22). Additional frequently mutated genes include RUNX1, GATA2, and SMAD4.22 Additional chromosome aberrations include trisomy 8, trisomy 10, or complex karyotype. This type of AML is often associated with a poor prognosis. |
| AML with CBFA2T3::GLIS2 | The dominant driver gene is the CBFA2T3::GLIS2 fusion resulting from chromosome inversion inv(16)(p13q24). Additional frequently mutated genes include FLT3, GATA1, KIT, KRAS, and NRAS.23 Additional chromosome aberrations include trisomy 21, hyperdiploid, or complex karyotype. This type of AML is often associated with a poor prognosis. |
| AML with NPM1 mutation | The dominant driver gene is the mutated NPM1, which is typically a 4-bp insertion in exon 12 of the gene. The mutated protein lost its nucleolar localization domain and is mislocated in the cytoplasm, which can be detected by an IHC assay. Additional frequently mutated genes include FLT3, NRAS, and WT1. Karyotype is typically normal. This type of AML is often associated with a favorable prognosis.24 |
| AML with CEBPA mutation | The dominant driver gene is the mutated CEBPA, which often involves both alleles (biCEBPA), however, for a single CEBPA mutation to be categorized in this group, it must be located in the basic leucine zipper (bZIP) region of the gene. BiCEBPA AML may be inherited. Additional frequently mutated genes include CSF3R, GATA2, KRAS, NRAS and FLT3. Karyotype is typically normal. This type of AML is typically associated with a favorable prognosis, but the presence of an additional CSF3R mutation can worsen the prognosis.25 |
Article Bibliography
| Reference Number | Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|---|
| 1 | 35159956 | 2022 | Pediatric Acute Myeloid Leukemia-Past, Present, and Future. | Reinhardt D et al |
| 2 | 31815781 | 2020 | Pediatric acute myeloid leukemia: updates on biology, risk stratification, and therapy. | Elgarten CW et al |
| 3 | 31803695 | 2019 | Targeted Therapies for Pediatric AML: Gaps and Perspective. | Lonetti A et al |
| 4 | 34420195 | 2021 | Targeted Therapy in Pediatric AML: An Evolving Landscape. | Jones LM et al |
| 5 | 35216084 | 2022 | Straight to the Point-The Novel Strategies to Cure Pediatric AML. | Lejman M et al |
| 6 | 32182684 | 2020 | Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene. | Liquori A et al |
| 7 | 31723813 | 2019 | Molecular characterization of AML with RUNX1-RUNX1T1 at diagnosis and relapse reveals net loss of co-mutations. | Höllein A et al |
| 8 | 34204358 | 2021 | Cytogenetics of Pediatric Acute Myeloid Leukemia: A Review of the Current Knowledge. | Quessada J et al |
| 9 | 35445594 | 2022 | Comprehensive Mutation Profile in Acute Myeloid Leukemia Patients with RUNX1-RUNX1T1 or CBFB-MYH11 Fusions. | Qin W et al |
| 10 | 31896782 | 2020 | The clinical mutatome of core binding factor leukemia. | Opatz S et al |
| 11 | 28701730 | 2018 | The MLL recombinome of acute leukemias in 2017. | Meyer C et al |
| 12 | 31681706 | 2019 | Pediatric Acute Myeloid Leukemia (AML): From Genes to Models Toward Targeted Therapeutic Intervention. | Mercher T et al |
| 13 | 25331116 | 2015 | EVI1-rearranged acute myeloid leukemias are characterized by distinct molecular alterations. | Lavallée VP et al |
| 14 | 24441146 | 2014 | t(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients. | Sandahl JD et al |
| 15 | 37011983 | 2023 | [Analysis of 7 cases of pediatric acute myeloid leukemia with DEK-NUP214 fusion gene]. | Li XL et al |
| 16 | 22162288 | 2012 | ETV6 rearrangements are recurrent in myeloid malignancies and are frequently associated with other genetic events. | Haferlach C et al |
| 17 | 29894279 | 2018 | Acute myeloid leukemia carrying ETV6 mutations: biologic and clinical features. | Zhou F et al |
| 18 | 29806701 | 2018 | Neonatal leukaemia. | Roberts I et al |
| 19 | 30759270 | 2019 | Acute myeloid leukemia with t(8;16)(p11.2;p13.3)/KAT6A-CREBBP in adults. | Xie W et al |
| 20 | 27694926 | 2017 | NUP98 is rearranged in 3.8% of pediatric AML forming a clinical and molecular homogenous group with a poor prognosis. | Struski S et al |
| 21 | 19287095 | 2009 | The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model. | Mercher T et al |
| 22 | 36181538 | 2022 | TLS/FUS-ERG fusion gene in acute leukemia and myelodysplastic syndrome evolved to acute leukemia: report of six cases and a literature review. | Zhang H et al |
| 23 | 28063190 | 2017 | Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non-Down syndrome. | Hara Y et al |
| 24 | 19569254 | 2009 | Nucleophosmin (NPM1) mutations in adult and childhood acute myeloid leukaemia: towards definition of a new leukaemia entity. | Rau R et al |
| 25 | 35178345 | 2022 | Acute Myeloid Leukemia With CEBPA Mutations: Current Progress and Future Directions. | Su L et al |
Citation
Sheng Xiao, MD ; Chunxiao Yang
Pediatric Acute myeloid leukaemias (AMLs) with recurrent genetic abnormalities
Atlas Genet Cytogenet Oncol Haematol. 2023-06-29
Online version: http://atlasgeneticsoncology.org/solid-tumor/209189/pediatric-acute-myeloid-leukaemias-(amls)-with-recurrent-genetic-abnormalities
