Skip to main content

Advertisement

We’d like to understand how you use our websites in order to improve them. Register your interest.

Clinical implications of recurrent gene mutations in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a genetically heterogeneous clonal malignancy characterized by recurrent gene mutations. Genomic heterogeneity, patients’ individual variability, and recurrent gene mutations are the major obstacles among many factors that impact treatment efficacy of the AML patients. With the application of cost- and time-effective next-generation sequencing (NGS) technologies, an enormous diversity of genetic mutations has been identified. The recurrent gene mutations and their important roles in acute myeloid leukemia (AML) pathogenesis have been studied extensively. In this review, we summarize the recent development on the gene mutation in patients with AML.

Introduction

Acute myeloid leukemia (AML) is a genetically heterogeneous clonal malignancy originating from clonal hematopoietic stem-cells, characterized by chromosomal abnormalities, recurrently gene mutations, epigenetic modifications affecting chromatin structure, and microRNAs deregulations. Genomic heterogeneity, patients’ individual variability, and recurrent gene mutations are the few major obstacles among many factors that impact treatment efficacy of the AML patients [1, 2].

With the application of new molecular techniques, such as cost- and time-effective next-generation sequencing (NGS) technologies, an enormous diversity of genetic mutations has been identified. Six genes, including FMS-like tyrosine kinase 3 (FLT3), nucleophosmin 1 (NPM1), CCAAT/enhancer binding protein alpha (CEBPA), Runt-related transcription factor 1 (RUNX1), additional sex combs-like 1 (ASXL1), and tumor protein p53 (TP53), have already been incorporated into the risk categories proposed by the European Leukemia Net (ELN) [2]. Other recurrent gene mutations have been reported in AML patients [3,4,5,6,7,8]. Furthermore, the important roles of recurrent gene mutation in AML pathogenesis had been explored and gene mutation-targeted therapies had been developed [8,9,10,11,12,13,14,15]. Certain genes have been proved to be specifically related to the leukemia pathogenesis, such as pre-leukemic cell identification, particularly in AML patients with mutated DNMT3A and TET2 [16, 17]. DNMT3A and TET2 are common mutated genes in patients with clonal hematopoiesis of indeterminate potential (CHIP) [18,19,20,21] and it might be considered as preleukemia cells identification markers [16, 17].

In this review, we summarize the recent development on the clinical implications of recurrent gene mutations in patients with AML.

FLT3

FLT3 is a type III receptor tyrosine kinase that plays an important role in hematopoietic cell survival, proliferation and differentiation. The important clinical point is that mutation of the FLT3 gene is the most frequent genetic alteration and a poor prognostic factor in AML patients. Mutations of the FLT3 gene occur in approximately 30% of all AML cases. There are two major types of FLT3 mutations: internal tandem duplication (FLT3-ITD) mutations in the juxtamembrane domain, which represents the most common type of FLT3 mutation occurring in approximately 25% of all AML cases, and point mutations or deletion in the tyrosine kinase domain (FLT3-TKD) occurring in approximately 7–10% of all cases with prognostic value uncertain [22,23,24,25,26]. Both mutant FLT3 molecules are activated through ligand-independent dimerization and trans-phosphorylation. Patients with FLT3-ITD have a high risk of relapse and low cure rates [22,23,24,25]. Risk associated to FLT3-ITD in patients with AML may depend on mutational burden and its interaction with other mutations. Allogeneic stem cell transplantation in first complete remission (CR1) was associated with a reduced relapse risk in all molecular subgroups with the exception of NPM1mut AML with absent or low ratio FLT3-ITD [27]. Another study showed patients with co-mutated NPM1 and FLT3-TKD may have an exceptionally favorable prognosis [28]. ELN-2017 guidelines recommend upfront testing for FLT3 and measurement of allele ratio (AR) for the prognosis risk stratification. For those patients with FLT+ testing, it’s important to incorporate targeted FLT3 inhibitors into the therapy regimen to improve the patients’ outcome [2]. Although FLT3–ITD–AR can be used for selecting patients for treatment with TKIs, but a relevance of ITD length may be the indicator for both outcome and response to FLT3-inhibitors. FLT3-ITD-AR on RNA measurement is recommended because superior prognostic value and accurate mRNA length measurement [2, 12]. Increasing FLT3-ITD AR and insertion site in the TKD1 were associated with low CR rates [23]. The insertion site was strongly correlated with ITD size: more C-terminal located inserted fragments were significantly bigger. A high mutant/wild-type ratio appears to have a major impact on the prognostic relevance [29]. Patients with more than one ITD had a significantly shorter OS and RFS [30].

Retrospective validation study of the ELN-2017 guidelines on the classification for AML with NPM1 and FLT3-ITD genotypes demonstrated that the ELN-2017 was more accurate to distinguish prognosis in patients with newly diagnosed AML [25]. However, when comparing patients with a low FLT3-ITD AR with those with a high FLT3-ITD AR, no significant differences in survival were noted in FLT3+ patients irrespective of NPM1 mutational status regardless of whether they were treated with intensive chemotherapy with or without a FLT3 inhibitor—a result that is discordant from the current ELN guidelines [25].

Other studies have demonstrated patients with mutations of FLT3-ITD, DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenases (IDH) 1, and ten-eleven translocation 2 (TET2) were risk factors for overall survival (OS) [4, 26]. The mutation patterns of Chinese AML patients by NGS revealed correlations between gene mutations and clinical features. Routine testing of suspected genes by NGS are recommended for better prognostic prediction and individualized treatment [4]. FLT3-ITD mutational status and KMT2E gene expression levels can be used to identify those AML patients who need to be treated differently to maximize their chances of cure [31]. RNA-based FLT3-ITD measurements are recommended for risk stratification, and the relevance of AR regarding eligibility for FLT3-targeted therapy remains uncertain [12].

Recent study demonstrates that PRMT1-mediated FLT3 methylation promotes AML maintenance and suggests that combining PRMT1 inhibition with FLT3 tyrosine kinase inhibitors treatment could be a promising approach to eliminate FLT3-ITD+ AML cells [32]. FLT3-TKD can activate the downstream effector molecule signal transducer and activator of transcription 5 (STAT5) exclusively in the presence of mutated NPM1c. NPM1c mislocalizes FLT3-TKD and changes its signal transduction ability [33].

Among those recurrent gene mutations, the most adverse prognosis was observed in patients with DNMT3A and FLT3-ITD co-mutation, whose survival could be significantly improved with allo-HSCT [7, 34]. Recurrent gene mutations analysis showed JAK2, FLT3-ITDhigh, and KIThigh mutations were identified as significant prognostic factors for OS in multivariate analysis [35]. FLT3-ITD mutant AR is closely related to CR and OS in AML patients. Classifying risk grades based on FLT3-ITD mutant AR is crucial for individualized treatment and prognostic evaluation [36]. Targeting mutant FLT3 by small molecule inhibitors has rapidly emerged as a new therapeutic approach in patients with AML. Different FLT3 inhibitor therapeutic agents have been developed and are summarized in Tables 1, 2 [9, 37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53].

Table 1 Gene mutation frequency and clinical implications
Table 2 Molecular target therapeutic agents

TP53

Mutations in transcription factor TP53 is important in cell cycle arrest for DNA mismatch repair, base excision repair, and nucleotide excision repair. TP53 gene mutation are present in < 10% of patients with de novo AML, 20–37% of patients with sAML/tAML, and up to 70% of patients with a complex karyotype. They are increasingly prevalent with relapsed/refractory (R/R) AML patients [54,55,56]. TP53 mutations are more frequent in older patients with a much lower complete remission rate comparing with patients without TP53 mutations. However, the dismal response to therapy appears irrespective of age, and is associated with decreased OS regardless of therapy [56]. Part of the dismal prognosis with TP53 mutations is in part due to the resistance to chemotherapy amongst this population [56]. Recent study showed that TP53 clearance at the time of allo-SCT was predictive of better outcomes in patients who had frontline hypomethylating agent therapy. For patients with persistent TP53 at the time of allo-SCT, those received myeloablative conditioning regimen experienced worse outcomes compared to reduced intensity conditioning regimen [57]. Residual TP53 mutation contributes to chemoresistance through clonal expansion in AML. Romidepsin itself or combined with others chemotherapy drugs can potentially cure or prevent residual p53 mutation caused chemoresistance and relapse in patient [58]. Targeting the TP53 pathway in addition to novel emerging therapeutics and immunotherapy-based approaches hold promise for treatment of TP53 mutant AML [59].

CEBPA

Transcription factor CCAAT/enhancer binding protein alpha (CEBPA) gene mutations have been found in approximately 10–20% of patients with cytogenetically normal AML, of which 50% with biallelic mutations (biCEBPA—in both N-terminal and C-terminal domains on separate alleles) [35, 60,61,62]. BiCEBPA has been recognized as a unique entity and recommended by ELN-2017 guidelines for upfront screening as favorable prognosis indicator with standard therapy [2, 35, 61, 62], and associated with improved event-free survival (EFS) and OS compared with all AML patients [40]. This benefit is notably exclusive to biCEBPA mutations patients, not to patients with single or monoallelic CEBPA (moCEBPA) genotypes [35, 61, 63]. CEBPA mutants have clonal heterogeneity as patients with biCEBPA are more likely to have co-mutations in TET2 and GATA2 (seen in ~ 30% of biCEBPA patients) [60, 63]. However, moCEBPA patients have a higher frequency of co-mutations in NPM1, FLT-3 ITD/TKD. IDH2 and TET2 mutations appear to confer an inferior prognosis amongst biCEBPA patients [60]. While CEBPA is currently not recommended as a marker of minimal residue disease (MRD), a specific leukemia-associated immunophenotype associated with biCEBPA mutations may serve as a valuable tool for screening and disease monitoring [64].

A recent large study on CEBPA mutations in pediatric AML showed that patients with a bZip mutation, regardless of single mutation vs. double mutations status, have a favorable prognosis. Furthermore, the study confirmed the significant overlap of CEBPA and CSF3R mutations, and demonstrated that CEBPA+/CSF3R+ patients were at high risk for relapse and thus should not be considered a low risk cohort. Given the poor outcomes with standard chemotherapy regimens, patients with CEBPA+/CSF3R+ mutations could be considered for addition of tyrosine kinase inhibitors with upfront therapy [65]. Flow cytometry detection of MRD may better predict the outcome rather than mutations based on NGS in AML with biCEBPA [63]. The WHO classification of AML with biCEBPA has been modified to require biallelic mutation of this gene, because only the biallelic mutation group is associated with an improved prognosis when compared to other AML types [66, 67]. This revised category is now considered a full entity, and supersedes AML with myelodysplasia-related changes in de novo cases [68]. Based on lineage restriction analysis, TET2 mutations could be detected in myeloid and B cells, but not T cells. DNMT3A mutations can be detected in myeloid, B and T cells in individuals with CHIP [21]. TET2 mutations have a bias towards myeloid proliferation, while DNMT3A mutations occur in multipotent stem cells. Both TET2 and CEBPA gene mutations had been used for the preleukemic cells identification [16, 17, 20, 21]. Additionally, germline CEBPA mutation has been identified in 4–15% of CEBPA double mutation AML and associated with the development of familial AML. A new category of “myeloid neoplasms with germline predisposition” has been provided by the new WHO classification and adopted by 2017 ELN Recommendations [2].

NPM1

NPM1 is frequently mutated and the incidence occur in up to 30% of AML patients overall and 40–60% of patients with normal karyotypes [3, 4, 60, 69]. Mutated NPM1 (mNPM1) is associated with a higher complete remission, improved OS, and a lower cumulative incidence of relapse [60]. ELN-2017 guidelines incorporate NPM1 screening at diagnosis given its favorable prognostication, particularly in the absence of co-occurring transmembrane FLT3-ITD mutations with a high AR [2]. Co-occurring mutations in FLT3-ITD occur approximately twice as often in patients with mNPM1 compared with wild type (wt) NPM1 (40.2% vs. 13.7%) [2, 70]. mNPM1 is also observed in approximately 60–70% of cases with DNTM3A mutations [70, 71]. NPM1 appears to be a stable marker for assessment of MRD [72]. NPM can also be involved in leukemogenic translocation including the t(3;5)(q25;q34) NPM–MLF1 translocation, which is associated to poor clinical course but remains undefined. Recent study finds NPM and the leukemogenic NPM–MLF1 play central role in chromatin organization and gene regulation in hematopoietic cells. Results suggest that the abnormal gene regulation forced by NPM–MLF1 is different than the loss of nuclear function imposed by NPMc+, and it can be characterized by the enhanced recruitment of CHD4/NuRD to genes. Thus, NPM–MLF1 is likely to promote hematopoietic malignancies by disruption of gene regulation imposed by the NuRD activity [10].

High NPM1 variant allele frequency (VAF) is correlated with shortened OS and EFS compared to the other NPM1 mutated cases. In both univariate and multivariable analyses, high NPM1 VAF had a particularly adverse prognostic effect in the subset of patients treated with stem-cell transplantation in first remission and in patients with mutated DNMT3A, indicating the prognostic effect of NPM1 mutation in de novo AML may be influenced by the relative abundance of the mutated allele [11]. Older patients with NPM1 mutated AML have distinctive genomic mutation landscape associated with enrichment in immunosuppressive gene signature [73]. NPM1/DNMT3A and NPM1/SRSF2 as additional mutation combinations might be useful for further group refinement [74].

RUNX1

RUNX1 is a transcription factor regulating critical processes in many aspects of hematopoiesis and is integral in defining the definitive hematopoietic stem cell. Located on chromosome 21, the RUNX1 gene is involved in many forms of chromosomal translocations in leukemia. t(8;21) is one of the most common chromosomal translocations found in AML, where it results in a fusion protein between RUNX1 and ETO. The RUNX1/ETO fusion protein is found in approximately 12% of all AML patients [75]. RUNX1/ETO maintains leukemia by promoting cell cycle progression and identifies G1 CCND-CDK complexes as promising therapeutic targets for treatment of RUNX1/ETO-driven AML [76]. Behaving mostly as loss-of-function mutations, they confer relative resistance to standard chemotherapy and are associated with unfavorable prognosis in AML [77].

As a core-binding factor of leukemia, RUNX1-RUNX1T1 had been recognized in AML and named as a new provisional entity “AML with mutated RUNX1” (excluding cases with myelodysplasia-related changes). RUNX1 mutation has been associated with distinct clinico-pathologic features and inferior outcome [2]. Mutations in DNMT3A and RUNX1 were associated only with inferior survival in younger (age < 60) patients [70].

Meta-analysis results showed that evidence supports clinical implications of RUNX1 mutations in the development and progression of AML cases and points to the possibility of a distinct category within the newer WHO classification. The findings suggest that the RUNX1 status can contribute to risk-stratification and decision-making in the management of AML [78]. Chemogenomic landscape of RUNX1-mutated AML reveals importance of RUNX1 allele dosage in genetics and glucocorticoid sensitivity. Results show the profound impact of RUNX1 allele dosage on gene expression profile and glucocorticoid sensitivity in AML, which may lead to drug repurposing and improved disease characterization [79].

IDH1/2

IDHs are enzymes involved in multiple metabolic and epigenetic cellular processes. Mutations in IDH1 or IDH2 are detected in approximately 20% of patients with AML and induce amino acid changes in conserved residues resulting in neomorphic enzymatic function and production of an oncometabolite, 2-hydroxyglutarate. This leads to DNA hypermethylation, aberrant gene expression, cell proliferation and abnormal differentiation. IDH mutations diversely affect prognosis of patients with AML based on the location of the mutation and other co-occurring genomic abnormalities. Recently, novel therapies specifically targeting mutant IDH have opened new avenues of therapy for these patients [80].

Recent work by flow cytometry and sequencing data has identified a distinct immunophenotypic subset of NPM1-mutated AML with TET2 or IDH1/2 mutations and improved outcome. This subset of NPM1-mutated AML was associated with longer relapse-free and OS, when compared with cases that were positive for CD34 and/or HLA-DR [81].

Targeting mutant IDH by small molecule inhibitors is a rapidly emerging therapeutic approach shown by the recent approval of the first selective mutant IDH2 inhibitor, enasidenib, for the treatment of IDH2-mutated AML [82]. Using mutant isocitrate dehydrogenase as a therapeutic drug target, selecting pan-mutant IDH1/2 inhibitors in clinical trials and other mutant IDH inhibitors are under development [82, 83]. In patients with advanced IDH1-mutated R/R AML, ivosidenib demonstrated durable remissions, and molecular remissions in some patients with complete remission [84]. Different IDH inhibitor therapeutic agents are summarized in Table 2 [85,86,87,88,89,90].

DNMT3A

DNMT3A is a kind of methyltransferase that is responsible for the de novo methylation of CpG dinucleotides. DNMT3A is crucial for the establishment and maintenance of cellular methylation patterns. The majority of the variants (approximately two-thirds of the cases) are located at R882 in exon 23. Study results have demonstrated that the DNMT3A R882 mutation disrupts the normal ligation of methyltransferase protein subunits, causing a dominant negative impact on DNMT3A protein function [91, 92]. Multiple researchers have confirmed that DNMT3A is frequently mutated in AML patients (13.5–23%) [3, 93, 94]. DNMT3A plays a unique role in hematopoiesis and AML pathogenesis as the inferior prognostic markers for AML patients [6, 95]. For other non-R882 mutations, especially for DNMT3A frameshift mutations, the occurrence is much less frequent and its prognostic significance is poorly understood [6]. AML patients with DNMT3A truncating mutations have comparable prognoses to those of DNMT3A wild type patients [96]. Distinct microRNA expression pattern for DNMT3A R882 AML patients might not only act as markers to predict disease prognosis, but also could be further investigated to develop novel therapeutic targets for patients with DNMT3A mutations [6].

DNMT3A and IDH2 mutations are synergistic events in leukemogenesis. Hematopoietic stem and progenitor cells carrying both mutations are sensitive to induced differentiation by the inhibition of both prostaglandin synthesis and HDAC [97]. However, the mutations in DNMT3A, commonly found in adults, were conspicuously absent from virtually all pediatric cases. This suggested the need for age-tailored targeted therapies for the treatment of pediatric AML [98]. Furthermore, a novel DNMT inhibitor, guadecitabine demonstrated improved pharmacokinetics and clinical activity in a subset of R/R AML patients [5].

KMT2A

AML patients with partial tandem duplications (PTDs) in the Mixed Lineage Leukemia (MLL) officially known as the Lysine (K)-specific methyltransferase 2A (KMT2A) gene, generally have adverse outcomes. KMT2A-PTDs occur in 3.2 to 11% of adult de novo AML and are more frequently present in AML with normal cytogenetics and AML with trisomy of chromosome 11 as a sole cytogenetic aberration [99, 100]. KMT2A-PTD alone appears insufficient to cause AML and additional genetic hits are required for the development of KMT2A-PTD leukemia [101, 102]. Homogeneously staining region on chromosome 11 is highly specific for KMT2A amplification in AML and MDS [103]. Molecular landscape analysis of KMT2A-PTD AML showed the specific HOX gene expression signatures. Concurrent DNMT3A mutations and NRAS mutations are associated with an adverse outcome [100]. Cytogenetic and molecular genetic characterization of KMT2A-PTD positive AML in comparison to KMT2A-rearranged AML demonstrated both KMT2A rearrangement (KMT2Ar) and KMT2A-PTD subtypes had unfavorable outcome, particularly in patients > 60 years. Patients with KMT2Ar were younger compared to patients with KMT2A-PTD and had a higher rate of additional cytogenetic abnormalities. In both groups, occurrence of additional cytogenetic abnormalities did not influence the OS [8].

ASXL1

As an epigenetic regulator, ASXL1 is one of the most frequently mutated genes in all subtypes of myeloid malignancies. ASXL1 mutations are also frequently detected in clonal hematopoiesis, which is associated with an increased risk of mortality [2, 104, 105]. ASXL1 mutations were associated with specific clinical and cytogenetic profiles of AML patients, such as older age, s-AML and higher peripheral leukocytosis, more frequent co-occurrence of ASXL1 mutations with trisomy 8 and chromosome 11 aberrations [106,107,108]. The VAF of ASXL1 and other mutations is associated with worse prognosis in patients with newly diagnosed AML [109].

Studies using ASXL1-depleted human hematopoietic cells and ASXL1 knockout mice have shown that deletion of wild-type ASXL1 protein leads to impaired hematopoiesis and accelerates myeloid malignancies via loss of interaction with polycomb repressive complex 2 proteins. On the other hand, ASXL1 mutations in myeloid neoplasms typically occur near the last exon and result in the expression of C-terminally truncated mutant ASXL1 protein [110]. There is also growing evidence indicating that the physiological expression of mutant ASXL1 protein perturbs hematopoiesis and promotes myeloid transformation by altering histone modifications in both dominant-negative and gain-of-function manners [111].

ASXL1 mutations in AML are more frequently coexist with RUNX1, IDH2 and other mutations [107, 108]. Notably, RUNX1 is the most frequently mutated gene in ASXL1-mutated AML. Coexistence of ASXL1 and RUNX1 mutations is related to poor prognosis in AML patients [107]. ASXL1 somatic mutation exists in hematological neoplasms including MDS, AML, MPN and MDS/MPN, and often is associated with somatic mutations of TET2, EZH2, IDH2, RUNX1, NRAS and DNMT3A. The pattern of clonal evolution suggests that this ASXL1 mutation might be an early mutational event that occurs in the principal clonal population and can serve as a clonal marker for R/R disease [112].

Mutations in genes encoding epigenetic modifiers, such as DNMT3A, ASXL1, TET2, IDH1, and IDH2, are commonly acquired early and are present in the founding clone. By contrast, mutations involving NPM1 or signaling molecules (e.g., FLT3, RAS gene family) are typically secondary events that occur later during leukaemogenesis [113, 114]. Novel promising therapeutic strategies had been established for targeting ASXL1 mutated myeloid malignancies by blocking interactions between ASXL1 and associating epigenetic regulators [115,116,117,118]. Furthermore, recurrent somatic mutations in more than 50 genes have been identified in 80–90% of MDS. The most recurrent genetic mutations are involved in the RNA splicing (e.g., SF3B1, SRSF2, U2AF1, ZRSR2, LUC7L2, DDX41) and epigenetic modifications, such as histone modification (e.g., ASXL1, EZH2) and DNA methylation (e.g., TET2, DNMT3A, IDH1/IDH2) [3, 119]. TP53 mutation predicts significant adverse clinical outcomes in MDS, however, clinical implications of other gene mutations remain unclear [119]. Recently, a lot of genomic information has been discovered in patients with AML and MDS, such as gene mutation with specific type of AML, genomic overlapping across different categories, even with the age-related frequency of selected recurring gene mutations [113]. However, the pathogenesis of AML caused by these gene mutations has yet to be further explored.

Conclusion

New understanding about the recurrent gene mutations in AML patients has been achieved regarding its clinical implications in the past years. Three recurrent gene mutations (RUNX1, ASXL1, and TP53) have been added in the risk stratification of the ELN-2017 recommendations for AML [2]. Recently, more novel fusion genes, such as GTF2I–PDGFRB and IKZF1–TYW1 fusion genes, and PAN2/PAN3 complex, have reported and may be clinically important [120, 121]. As the new technology advances, more recurrent gene mutations will be explored and used for AML risk stratification and treatment guidelines. Furthermore, gene mutation-targeted new drugs and therapies will be developed and benefit more AML patients in the near future.

Availability of data and materials

Not applicable.

Abbreviations

AML:

Acute myeloid leukemia

AR:

Allele ratio

ASXL1:

Additional sex combs-like 1

biCEBPA:

Biallelic mutations of CCAAT/enhancer binding protein alpha

CEBPA:

CCAAT/enhancer binding protein alpha

CHIP:

Clonal hematopoiesis of indeterminate potential

CR1:

First complete remission

DNMT3A:

DNA methyltransferase 3A

EFS:

Event-free survival

ELN:

European Leukemia Net

FLT3:

FMS-like tyrosine kinase 3

FLT3-ITD:

FLT3 mutations: internal tandem duplication

FLT3-TKD:

FLT3 mutations: tyrosine kinase domain

IDH:

Isocitrate dehydrogenases

KMT2A:

Lysine (K)-specific methyltransferase 2A

moCEBPA:

Monoallelic mutations of CCAAT/enhancer binding protein alpha

MRD:

Minimal residual disease

NGS:

Next-generation sequencing

NPM1:

Nucleophosmin

OS:

Overall survival

R/R:

Relapsed/refractory

RUNX1:

Runt-related transcription factor 1

STAT5:

Signal transducer and activator of transcription 5

TP53:

Tumor protein p53

VAF:

Variant allele frequency

References

  1. 1.

    Chen J, Odenike O, Rowley JD. Leukaemogenesis: more than mutant genes. Nat Rev Cancer. 2010;10(1):23–36.

  2. 2.

    Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–47.

  3. 3.

    Yu J, Li Y, Li T, Li Y, Xing H, Sun H, et al. Gene mutational analysis by NGS and its clinical significance in patients with myelodysplastic syndrome and acute myeloid leukemia. Exp Hematol Oncol. 2020;6(9):2.

  4. 4.

    Han X, Li W, He N, Feng P, Pang Y, Ji C, et al. Gene mutation patterns of Chinese acute myeloid leukemia patients by targeted next-generation sequencing and bioinformatic analysis. Clin Chim Acta. 2018;479:25–37.

  5. 5.

    Chung W, Kelly AD, Kropf P, Fung H, Jelinek J, Su XY, et al. Genomic and epigenomic predictors of response to guadecitabine in relapsed/refractory acute myelogenous leukemia. Clin Epigenet. 2019;11(1):106.

  6. 6.

    Yang L, Shen K, Zhang M, Zhang W, Cai H, Lin L, et al. Clinical features and microRNA expression patterns between AML patients with DNMT3A R882 and frameshift mutations. Front Oncol. 2019;24(9):1133.

  7. 7.

    Folta A, Culen M, Jeziskova I, Herudkova Z, Tom N, Hlubinkova T, et al. Prognostic significance of mutation profile at diagnosis and mutation persistence during disease remission in adult acute myeloid leukaemia patients. Br J Haematol. 2019;186(2):300–10.

  8. 8.

    Vetro C, Haferlach T, Meggendorfer M, Stengel A, Jeromin S, Kern W, et al. Cytogenetic and molecular genetic characterization of KMT2A-PTD positive acute myeloid leukemia in comparison to KMT2A-rearranged acute myeloid leukemia. Cancer Genet. 2020;240:15–22.

  9. 9.

    Antar AI, Otrock ZK, Jabbour E, Mohty M, Bazarbachi A. FLT3 inhibitors in acute myeloid leukemia: ten frequently asked questions. Leukemia. 2020. https://doi.org/10.1038/s41375-019-0694-3.

  10. 10.

    Darracq A, Pak H, Bourgoin V, Zmiri F, Dellaire G, Affar EB, et al. NPM and NPM-MLF1 interact with chromatin remodeling complexes and influence their recruitment to specific genes. PLoS Genet. 2019;15(11):e1008463.

  11. 11.

    Patel SS, Kuo FC, Gibson CJ, Steensma DP, Soiffer RJ, Alyea EP 3rd, et al. High NPM1-mutant allele burden at diagnosis predicts unfavorable outcomes in de novo AML. Blood. 2018;131(25):2816–25.

  12. 12.

    Cucchi DGJ, Denys B, Kaspers GJL, Janssen JJWM, Ossenkoppele GJ, de Haas V, et al. RNA-based FLT3-ITD allelic ratio is associated with outcome and ex vivo response to FLT3 inhibitors in pediatric AML. Blood. 2018;131(22):2485–9.

  13. 13.

    Boileau M, Shirinian M, Gayden T, Harutyunyan AS, Chen CCL, Mikael LG, et al. Mutant H3 histones drive human pre-leukemic hematopoietic stem cell expansion and promote leukemic aggressiveness. Nat Commun. 2019;10(1):2891.

  14. 14.

    Tallman M. Prognostic significance of molecular markers and targeted regimens in the management of acute myeloid leukemia. J Natl Compr Canc Netw. 2018;16(5S):656–9.

  15. 15.

    Tallman MS, Wang ES, Altman JK, Appelbaum FR, Bhatt VR, Bixby D, et al. Acute myeloid leukemia, version 3.2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2019;17(6):721–49.

  16. 16.

    Corces-Zimmerman MR, Hong WJ, Weissman IL, Medeiros BC, Majeti R. Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Natl Acad Sci USA. 2014;111(7):2548–53.

  17. 17.

    Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V, et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature. 2014;506(7488):328–33.

  18. 18.

    Genovese G, Kähler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371(26):2477–87.

  19. 19.

    Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488–98.

  20. 20.

    Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20(12):1472–8.

  21. 21.

    Buscarlet M, Provost S, Zada YF, Bourgoin V, Mollica L, Dubé MP, et al. Lineage restriction analyses in CHIP indicate myeloid bias for TET2 and multipotent stem cell origin for DNMT3A. Blood. 2018;132(3):277–80.

  22. 22.

    Ponziani V, Gianfaldoni G, Mannelli F, Leoni F, Ciolli S, Guglielmelli P, et al. The size of duplication does not add to the prognostic significance of FLT3 internal tandem duplication in acute myeloid leukemia patients. Leukemia. 2006;20(11):2074–6.

  23. 23.

    Schlenk RF, Kayser S, Bullinger L, Kobbe G, Casper J, Ringhoffer M, et al. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood. 2014;124(23):3441–9.

  24. 24.

    Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, et al. Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol. 2010;28(28):4339–45.

  25. 25.

    Boddu PC, Kadia TM, Garcia-Manero G, Cortes J, Alfayez M, Borthakur G, et al. Validation of the 2017 European LeukemiaNet classification for acute myeloid leukemia with NPM1 and FLT3-internal tandem duplication genotypes. Cancer. 2019;125(7):1091–100.

  26. 26.

    Niparuck P, Limsuwanachot N, Pukiat S, Chantrathammachart P, Rerkamnuaychoke B, Magmuang S, et al. Cytogenetics and FLT3-ITD mutation predict clinical outcomes in non transplant patients with acute myeloid leukemia. Exp Hematol Oncol. 2019;30(8):3.

  27. 27.

    Pratcorona M, Brunet S, Nomdedéu J, Ribera JM, Tormo M, Duarte R, et al. Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy. Blood. 2013;121(14):2734–8.

  28. 28.

    Boddu P, Kantarjian H, Borthakur G, Kadia T, Daver N, Pierce S, et al. Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group. Blood Adv. 2017;1(19):1546–50.

  29. 29.

    Blau O, Berenstein R, Sindram A, Blau IW. Molecular analysis of different FLT3-ITD mutations in acute myeloid leukemia. Leuk Lymphoma. 2013;54(1):145–52. https://doi.org/10.3109/10428194.2012.704999.

  30. 30.

    Schranz K, Hubmann M, Harin E, Vosberg S, Herold T, Metzeler KH, et al. Clonal heterogeneity of FLT3-ITD detected by high-throughput amplicon sequencing correlates with adverse prognosis in acute myeloid leukemia. Oncotarget. 2018;9(53):30128–45.

  31. 31.

    Lucena-Araujo AR, Coelho-Silva JL, Pereira-Martins DA, Silveira DR, Koury LC, Melo RAM, et al. Combining gene mutation with gene expression analysis improves outcome prediction in acute promyelocytic leukemia. Blood. 2019;134(12):951–9.

  32. 32.

    He X, Zhu Y, Lin YC, Li M, Du J, Dong H, et al. PRMT1-mediated FLT3 arginine methylation promotes maintenance of FLT3-ITD+ acute myeloid leukemia. Blood. 2019;134(6):548–60.

  33. 33.

    Rudorf A, Müller TA, Klingeberg C, Kreutmair S, Poggio T, Gorantla SP, et al. NPM1c alters FLT3-D835Y localization and signaling in acute myeloid leukemia. Blood. 2019;134(4):383–8.

  34. 34.

    Wang H, Chu TT, Han SY, Qi JQ, Tang YQ, Qiu HY, et al. FLT3-ITD and CEBPA mutations predict prognosis in acute myelogenous leukemia irrespective of hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2019;25(5):941–8.

  35. 35.

    Christen F, Hoyer K, Yoshida K, Hou HA, Waldhueter N, Heuser M, et al. Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients. Blood. 2019;133(10):1140–51.

  36. 36.

    Lyu M, Liao H, Shuai X, Jin Y, Su J, Zheng Q. The prognosis predictive value of FMS-like tyrosine kinase 3-internal tandem duplications mutant allelic ratio (FLT3-ITD MR) in patients with acute myeloid leukemia detected by GeneScan. Gene. 2020;5(726):144195.

  37. 37.

    Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454–64.

  38. 38.

    Schlenk RF, Weber D, Fiedler W, Salih HR, Wulf G, Salwender H, et al. Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood. 2019;133(8):840–51.

  39. 39.

    Shimada A. Hematological malignancies and molecular targeting therapy. Eur J Pharmacol. 2019;862:172641.

  40. 40.

    Fiedler W, Kayser S, Kebenko M, Janning M, Krauter J, Schittenhelm M, et al. A phase I/II study of sunitinib and intensive chemotherapy in patients over 60 years of age with acute myeloid leukaemia and activating FLT3 mutations. Br J Haematol. 2015;169(5):694–700.

  41. 41.

    Fiedler W, Serve H, Döhner H, Schwittay M, Ottmann OG, O’Farrell AM, et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood. 2005;105(3):986–93.

  42. 42.

    Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381(18):1728–40.

  43. 43.

    Sidaway P. Gilteritinib improves outcomes in AML. Nat Rev Clin Oncol. 2020;17(2):69.

  44. 44.

    Knapper S, Russell N, Gilkes A, Hills RK, Gale RE, Cavenagh JD, et al. A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML. Blood. 2017;129(9):1143–54.

  45. 45.

    Levis M, Ravandi F, Wang ES, Baer MR, Perl A, Coutre S, et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood. 2011;117(12):3294–301.

  46. 46.

    Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, et al. Internal tandem duplication of the FLT3 gene found in acute myeloid leukemia. Leukemia. 1996;10:1911–8.

  47. 47.

    Wang ES. Incorporating FLT3 inhibitors in the frontline treatment of FLT3 mutant acute myeloid leukemia. Best Pract Res Clin Haematol. 2019;32(2):154–62.

  48. 48.

    Cortes JE, Tallman MS, Schiller GJ, Trone D, Gammon G, Goldberg SL, et al. Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD-mutated, relapsed or refractory AML. Blood. 2018;132(6):598–607.

  49. 49.

    Cortes J, Perl AE, Döhner H, Kantarjian H, Martinelli G, Kovacsovics T, et al. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2018;19(7):889–903.

  50. 50.

    Zhou F, Ge Z, Chen B. Quizartinib (AC220): a promising option for acute myeloid leukemia. Drug Des Dev Ther. 2019;13:1117–25.

  51. 51.

    Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, et al. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019;20(7):984–97.

  52. 52.

    Sasaki K, Kantarjian HM, Kadia T, Patel K, Loghavi S, Garcia-Manero G, et al. Sorafenib plus intensive chemotherapy improves survival in patients with newly diagnosed, FLT3-internal tandem duplication mutation-positive acute myeloid leukemia. Cancer. 2019;125(21):3755–66.

  53. 53.

    Xuan L, Wang Y, Chen J, Jiang E, Gao L, Wu B, et al. Sorafenib therapy is associated with improved outcomes for FMS-like tyrosine kinase 3 internal tandem duplication acute myeloid leukemia relapsing after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2019;25(8):1674–81.

  54. 54.

    Ok CY, Patel KP, Garcia-Manero G, Routbort MJ, Peng J, Tang G, et al. TP53 mutation characteristics in therapy-related myelodysplastic syndromes and acute myeloid leukemia is similar to de novo diseases. J Hematol Oncol. 2015;8(8):45.

  55. 55.

    Zhang L, McGraw KL, Sallman DA, List AF. The role of p53 in myelodysplastic syndromes and acute myeloid leukemia: molecular aspects and clinical implications. Leuk Lymphoma. 2017;58(8):1777–90.

  56. 56.

    Kadia TM, Jain P, Ravandi F, Garcia-Manero G, Andreef M, Takahashi K, et al. TP53 mutations in newly diagnosed acute myeloid leukemia: clinicomolecular characteristics, response to therapy, and outcomes. Cancer. 2016;122(22):3484–91.

  57. 57.

    Chan O, Hunter A, Talati C, Sallman DA, Asghari H, Song J, et al. Impact of TP53 gene mutation clearance and conditioning intensity on outcome in MDS or AML patients prior to allogeneic stem cell transplantation. Blood. 2019;134(Supplement_1):149.

  58. 58.

    Yan B, Chen Q, Xu J, Li W, Xu B, Huang S, et al. Residual TP53 mutation contributes to chemoresistance through clonal expansion in acute myeloid leukemia. Blood. 2019;134(Supplement_1):2731.

  59. 59.

    Asghari H, Talati C. Tumor protein 53 mutations in acute myeloid leukemia: conventional induction chemotherapy or novel therapeutics. Curr Opin Hematol. 2020;27(2):66–75.

  60. 60.

    Konstandin NP, Pastore F, Herold T, Dufour A, Rothenberg-Thurley M, Hinrichsen T, et al. Genetic heterogeneity of cytogenetically normal AML with mutations of CEBPA. Blood Adv. 2018;2(20):2724–31.

  61. 61.

    Li HY, Deng DH, Huang Y, Ye FH, Huang LL, Xiao Q, et al. Favorable prognosis of biallelic CEBPA gene mutations in acute myeloid leukemia patients: a meta-analysis. Eur J Haematol. 2015;94(5):439–48.

  62. 62.

    Dufour A, Schneider F, Metzeler KH, Hoster E, Schneider S, Zellmeier E, Benthaus T, Sauerland MC, et al. Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome. J Clin Oncol. 2010;28(4):570–7.

  63. 63.

    Greif PA, Dufour A, Konstandin NP, Ksienzyk B, Zellmeier E, Tizazu B, et al. GATA2 zinc finger 1 mutations associated with biallelic CEBPA mutations define a unique genetic entity of acute myeloid leukemia. Blood. 2012;120(2):395–403.

  64. 64.

    Mannelli F, Ponziani V, Bencini S, Bonetti MI, Benelli M, Cutini I, et al. CEBPA-double-mutated acute myeloid leukemia displays a unique phenotypic profile: a reliable screening method and insight into biological features. Haematologica. 2017;102(3):529–40.

  65. 65.

    Tarlock K, Alonzo TA, Wang YC, Gerbing RB, Ries RE, Hylkema TA, et al. Somatic Bzip mutations of CEBPA are associated with favorable outcome regardless of presence as single vs double mutation. Blood. 2019;134(Supplement_1):181.

  66. 66.

    Green CL, Koo KK, Hills RK, Burnett AK, Linch DC, Gale RE. Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations. J Clin Oncol. 2010;28(16):2739–47.

  67. 67.

    Hollink IH, van den Heuvel-Eibrink MM, Arentsen-Peters ST, Zimmermann M, Peeters JK, Valk PJ, et al. Characterization of CEBPA mutations and promoter hypermethylation in pediatric acute myeloid leukemia. Haematologica. 2011;96(3):384–92.

  68. 68.

    Arber DA. The 2016 WHO classification of acute myeloid leukemia: what the practicing clinician needs to know. Semin Hematol. 2019;56(2):90–5.

  69. 69.

    Chan SM, Majeti R. Role of DNMT3A, TET2, and IDH1/2 mutations in pre-leukemic stem cells in acute myeloid leukemia. Int J Hematol. 2013;98(6):648–57.

  70. 70.

    Metzeler KH, Herold T, Rothenberg-Thurley M, Amler S, Sauerland MC, Görlich D, et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood. 2016;128(5):686–98.

  71. 71.

    Heath EM, Chan SM, Minden MD, Murphy T, Shlush LI, Schimmer AD. Biological and clinical consequences of NPM1 mutations in AML. Leukemia. 2017;31(4):798–807.

  72. 72.

    Ivey A, Hills RK, Simpson MA, Jovanovic JV, Gilkes A, Grech A, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016;374(5):422–33.

  73. 73.

    Abdelhakim H, Elkhanany A, Telfah M, Lin TL, Godwin AK. Older patients with NPM1 mutated AML have distinctive genomic mutation landscape associated with enrichment in immunosuppressive gene signature. Blood. 2019;134(Supplement_1):1402.

  74. 74.

    Eisfeld AK, Kohlschmidt J, Mrózek K, Nicolet D, Mims AS, Papaioannou D, et al. The 2017 European leukemianet genetic risk classification performs poorly in older patients with acute myeloid leukemia (AML) and should be refined to identify patients requiring additional or alternative treatment. Blood. 2019;134(Supplement_1):2681.

  75. 75.

    Lam K, Zhang DE. RUNX1 and RUNX1-ETO: roles in hematopoiesis and leukemogenesis. Front Biosci. 2012;17:1120–39.

  76. 76.

    Martinez-Soria N, McKenzie L, Draper J, Ptasinska A, Issa H, Potluri S, et al. The oncogenic transcription factor RUNX1/ETO corrupts cell cycle regulation to drive leukemic transformation. Cancer Cell. 2018;34(4):626.e8–642.e8.

  77. 77.

    Schnittger S, Dicker F, Kern W, Wendland N, Sundermann J, Alpermann T, et al. RUNX1 mutations are frequent in de novo AML with noncomplex karyotype and confer an unfavorable prognosis. Blood. 2011;117(8):2348–57.

  78. 78.

    Jalili M, Yaghmaie M, Ahmadvand M, Alimoghaddam K, Mousavi SA, Vaezi M, et al. Prognostic value of RUNX1 mutations in AML: a meta-analysis. Asian Pac J Cancer Prev. 2018;19(2):325–9.

  79. 79.

    Simon L, Lavallée VP, Bordeleau ME, Krosl J, Baccelli I, Boucher G, et al. Chemogenomic landscape of RUNX1-mutated AML reveals importance of RUNX1 allele dosage in genetics and glucocorticoid sensitivity. Clin Cancer Res. 2017;23(22):6969–81.

  80. 80.

    Montalban-Bravo G, DiNardo CD. The role of IDH mutations in acute myeloid leukemia. Future Oncol. 2018;14(10):979–93.

  81. 81.

    Mason EF, Kuo FC, Hasserjian RP, Seegmiller AC, Pozdnyakova O. A distinct immunophenotype identifies a subset of NPM1-mutated AML with TET2 or IDH1/2 mutations and improved outcome. Am J Hematol. 2018;93(4):504–10.

  82. 82.

    Sharma H. Development of novel therapeutics targeting isocitrate dehydrogenase mutations in cancer. Curr Top Med Chem. 2018;18(6):505–24.

  83. 83.

    Medeiros BC, Fathi AT, DiNardo CD, Pollyea DA, Chan SM, Swords R. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia. 2017;31(2):272–81.

  84. 84.

    Roboz GJ, DiNardo CD, Stein EM, de Botton S, Mims AS, Prince GT, et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood. 2019. https://doi.org/10.1182/blood.2019002140.

  85. 85.

    DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386–98.

  86. 86.

    Stein EM, DiNardo CD, Fathi AT, Pollyea DA, Stone RM, Altman JK, Roboz GJ, Patel MR, Collins R, Flinn IW, Sekeres MA, Stein AS, Kantarjian HM, Levine RL, Vyas P, MacBeth KJ, Tosolini A, Van Oostendorp J, Xu Q, Gupta I, Lila T, Risueno A, Yen KE, Wu B, Attar EC, Tallman MS, de Botton S. Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib. Blood. 2019;133(7):676–87. https://doi.org/10.1182/blood-2018-08-869008.

  87. 87.

    Pollyea DA, Tallman MS, de Botton S, Kantarjian HM, Collins R, Stein AS, et al. Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia. 2019;33(11):2575–84. https://doi.org/10.1038/s41375-019-0472-2.

  88. 88.

    Abou Dalle I, DiNardo CD. The role of enasidenib in the treatment of mutant IDH2 acute myeloid leukemia. Ther Adv Hematol. 2018;9(7):163–73.

  89. 89.

    Reed DR, Elsarrag RZ, Morris AL, Keng MK. Enasidenib in acute myeloid leukemia: clinical development and perspectives on treatment. Cancer Manag Res. 2019;11:8073–80.

  90. 90.

    Watts JM, Baer MR, Yang J, Prebet T, Lee S, Schiller GJ, et al. Olutasidenib (FT-2102), an IDH1m inhibitor as a single agent or in combination with azacitidine, induces deep clinical researches with mutation clearance in patients with acute myeloid leukemia treated in a phase 1 dose escalation and expansion study. In: Presented at the 61st annual meeting of the American Society of Hematology, December 7–10, 2019, Orlando, FL (abstract 616).

  91. 91.

    Holz-Schietinger C, Matje DM, Reich NO. Mutations in DNA methyltransferase (DNMT3A) observed in acute myeloid leukemia patients disrupt processive methylation. J Biol Chem. 2012;287(37):30941–51.

  92. 92.

    Kim SJ, Zhao H, Hardikar S, Singh AK, Goodell MA, Chen T. A DNMT3A mutation common in AML exhibits dominant-negative effects in murine ES cells. Blood. 2013;122(25):4086–9.

  93. 93.

    Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363:2424–33.

  94. 94.

    Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366:1079–89.

  95. 95.

    Gaidzik VI, Schlenk RF, Paschka P, Stölzle A, Späth D, Lilienfeld-Toal M, et al. Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML study group (AMLSG). Blood. 2013;121:4769–77.

  96. 96.

    Gale RE, Lamb K, Allen C, El-Sharkawi D, Stowe C, Jenkinson S, et al. Simpson’s paradox and the impact of different DNMT3A mutations on outcome in younger adults with acute myeloid leukemia. J Clin Oncol. 2015;33(18):2072–83.

  97. 97.

    Zhang X, Wang X, Wang XQD, Su J, Putluri N, Zhou T, et al. Dnmt3a loss and Idh2 neomorphic mutations mutually potentiate malignant hematopoiesis. Blood. 2020. https://doi.org/10.1182/blood.2019003330.

  98. 98.

    Bolouri H, Farrar JE, Triche T Jr, Ries RE, Lim EL, Alonzo TA, et al. The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Nat Med. 2018;24(1):103–12.

  99. 99.

    Basecke J, Whelan JT, Griesinger F, Bertrand FE. The MLL partial tandem duplication in acute myeloid leukaemia. Br J Haematol. 2006;135(4):438–49. https://doi.org/10.1111/j.1365-2141.2006.06301.x.

  100. 100.

    Hinai ASAA, Pratcorona M, Grob T, Kavelaars FG, Bussaglia E, Sanders MA, et al. The landscape of KMT2A-PTD AML: concurrent mutations, gene expression signatures, and clinical outcome. Hemasphere. 2019;3(2):e181.

  101. 101.

    Zhang Y, Yan X, Sashida G, Zhao X, Rao Y, Goyama S, et al. Stress hematopoiesis reveals abnormal control of self-renewal, lineage bias, and myeloid differentiation in Mll partial tandem duplication (Mll-PTD) hematopoietic stem/progenitor cells. Blood. 2012;120(5):1118–29.

  102. 102.

    Gilliland DG. Hematologic malignancies. Curr Opin Hematol. 2001;8(4):189–91.

  103. 103.

    Sakhdari A, Tang Z, Ok CY, Bueso-Ramos CE, Medeiros LJ, Huh YO. Homogeneously staining region (hsr) on chromosome 11 is highly specific for KMT2A amplification in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Cancer Genet. 2019;238:18–22.

  104. 104.

    Schnittger S, Eder C, Jeromin S, Alpermann T, Fasan A, Grossmann V, et al. ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome. Leukemia. 2013;27(1):82–91.

  105. 105.

    Metzeler KH, Becker H, Maharry K, Radmacher MD, Kohlschmidt J, Mrózek K, et al. ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN favorable genetic category. Blood. 2011;118(26):6920–9.

  106. 106.

    Kakosaiou K, Panitsas F, Daraki A, Pagoni M, Apostolou P, Ioannidou A, et al. ASXL1 mutations in AML are associated with specific clinical and cytogenetic characteristics. Leuk Lymphoma. 2018;59(10):2439–46.

  107. 107.

    Paschka P, Schlenk RF, Gaidzik VI, Herzig JK, Aulitzky T, Bullinger L, et al. ASXL1 mutations in younger adult patients with acute myeloid leukemia: a study by the German-Austrian acute myeloid leukemia study group. Haematologica. 2015;100(3):324–30.

  108. 108.

    Chou WC, Huang HH, Hou HA, Chen CY, Tang JL, Yao M, et al. Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations. Blood. 2010;116(20):4086–94.

  109. 109.

    Sasaki K, Kanagal-Shamanna R, Montalban-Bravo G, Assi R, Jabbour E, Ravandi F, et al. Impact of the variant allele frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the outcomes of patients with newly diagnosed acute myeloid leukemia. Cancer. 2020;126(4):765–74.

  110. 110.

    Asada S, Fujino T, Goyama S, Kitamura T. The role of ASXL1 in hematopoiesis and myeloid malignancies. Cell Mol Life Sci. 2019;76(13):2511–23.

  111. 111.

    Nagase R, Inoue D, Pastore A, Fujino T, Hou HA, Yamasaki N, et al. Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation. J Exp Med. 2018;215(6):1729–47.

  112. 112.

    Montes-Moreno S, Routbort MJ, Lohman EJ, Barkoh BA, Kanagal-Shamanna R, Bueso-Ramos CE, et al. Clinical molecular testing for ASXL1 c.1934dupG p.Gly646fs mutation in hematologic neoplasms in the NGS era. PLoS ONE. 2018;13(9):e0204218.

  113. 113.

    Bullinger L, Döhner K, Döhner H. Genomics of acute myeloid leukemia diagnosis and pathways. J Clin Oncol. 2017;35(9):934–46.

  114. 114.

    Medinger M, Passweg JR. Acute myeloid leukaemia genomics. Br J Haematol. 2017;179(4):530–42.

  115. 115.

    Asada S, Goyama S, Inoue D, Shikata S, Takeda R, Fukushima T, et al. Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis. Nat Commun. 2018;9(1):2733.

  116. 116.

    Inoue D, Fujino T, Sheridan P, Zhang YZ, Nagase R, Horikawa S, et al. A novel ASXL1-OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies. Leukemia. 2018;32(6):1327–37.

  117. 117.

    Saika M, Inoue D, Nagase R, Sato N, Tsuchiya A, Yabushita T, et al. ASXL1 and SETBP1 mutations promote leukaemogenesis by repressing TGFβ pathway genes through histone deacetylation. Sci Rep. 2018;8(1):15873.

  118. 118.

    Yang H, Kurtenbach S, Guo Y, Lohse I, Durante MA, Li J, et al. Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies. Blood. 2018;131(3):328–41.

  119. 119.

    Hosono N. Genetic abnormalities and pathophysiology of MDS. Int J Clin Oncol. 2019;24(8):885–92.

  120. 120.

    Panagopoulos I, Gorunova L, Andersen HK, Bergrem A, Dahm A, Andersen K, et al. PAN3-PSMA2 fusion resulting from a novel t(7;13)(p14;q12) chromosome translocation in a myelodysplastic syndrome that evolved into acute myeloid leukemia. Exp Hematol Oncol. 2018;20(7):7.

  121. 121.

    Panagopoulos I, Brunetti M, Stoltenberg M, Strandabø RAU, Staurseth J, Andersen K, et al. Novel GTF2I-PDGFRB and IKZF1-TYW1 fusions in pediatric leukemia with normal karyotype. Exp Hematol Oncol. 2019;29(8):12.

Download references

Acknowledgements

We thank Dr. Delong Liu of New York Medical College and Dr. Kongming Wu of Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology for helpful discussion and language editing assistance.

Funding

This study was funded by the Key Scientific Research Project of Henan Provincial Education Department (19A320046 and 20A320062); National Natural Science Foundation of China (U1804192) and Special Talents Project Fund of the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. The funding bodies did not participate in study design, in data collection, analysis, and interpretation, and in writing the manuscript.

Author information

Affiliations

Authors

Contributions

All authors contributed to drafting and revising the article and agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jifeng Yu or Zhongxing Jiang.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yu, J., Li, Y., Zhang, D. et al. Clinical implications of recurrent gene mutations in acute myeloid leukemia. Exp Hematol Oncol 9, 4 (2020). https://doi.org/10.1186/s40164-020-00161-7

Download citation

Keywords

  • Recurrent gene mutation
  • Acute myeloid leukemia (AML)
  • FLT3
  • CEBPA
  • NPM1
  • RUNX1
  • ASXL1
  • TP53
  • IDH1/2