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Relationship between gene mutations and fusion genes of FLT3-ITD and FLT3-TKD AML. a, b Represent fusion genes by targeted NGS and its exclusive relationship with NPM1 mutation in FLT3-ITD positive AML (n = 60). c, d Represent fusion genes by targeted NGS and its exclusive relationship with NPM1 mutation in FLT3-TKD positive AML (n = 16)
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Background
The receptor tyrosine kinase FLT3 with internal tandem duplications within the juxtamembrane domain ( FLT3 -ITD) is a poor prognostic factor; however, the prognostic significance of missense mutation in the tyrosine kinase domain ( FLT3 -TKD) is controversial. Furthermore, the accompanying mutations and fusion genes with FLT3 mutations a...
Contexts in source publication
Context 1
... the 52 patients with FLT3-ITD, 21 had fusion genes, and the incidence of fusion genes was 40.4% ( Fig. 2a, b). The most common fusion genes of FLT3-ITD AML included seven MLL-rearranged (13.5%) (four MLL-PTD, two MLL-AF9, and one MLL-ELL) and seven NUP98-rearranged (13.5%) (four NUP98-NSD1 and three NUP98-HOX9A). Other recurrent fusions included three with AML1-ETO and two with DEK/CAN. One case with PRDM16-SKI and one case with EFAN2-ZNF238 ...
Context 2
... the 16 FLT3-TKD mutant AML patients, 11 cases had fusion genes (four cases with AML1-ETO, two cases with MLL-AF9, one case with AML1-MDS1, one case with DEC-CAN, one case with BCR-ABL, one case with CBFB-MYH11, and one case with MLL-TMX2 -CTNND1) (Fig. 2c, d). The frequency of fusion genes of FLT3-TKD group was higher than that of FLT3-ITD group (68.75% vs. 40.4%, P = 0.014). Among patients with FLT3-TKD, 11 patients were associated with fusion genes, as described in the manuscript, four cases with AML1-ETO, two cases with MLL-AF9, one case with AML1-MDS1, one case with DEC-CAN, one case ...
Context 3
... AML patients with FLT3-ITD, NPM1 and DNMT3A were the most common mutations. FLT3-ITD with both NPM1 and DNMT3A mutations defines a poor prognosis. Three-year OS of FLT3-ITD patients with both NPM1 and DNMT3A mutations was 12.7% ± 11.5% (Additional file 2: Fig. S2A), though no significant difference was observed between the four subgroups in FLT3-ITD patients in DFS (Additional file 2: Fig. ...
Context 4
... were the most common mutations. FLT3-ITD with both NPM1 and DNMT3A mutations defines a poor prognosis. Three-year OS of FLT3-ITD patients with both NPM1 and DNMT3A mutations was 12.7% ± 11.5% (Additional file 2: Fig. S2A), though no significant difference was observed between the four subgroups in FLT3-ITD patients in DFS (Additional file 2: Fig. ...
Context 5
... mutation and fusion genes rarely occurred simultaneously in FLT3 mutant patients (Figs. 2, 5). Only two patients with FLT3-ITD are accompanied by both NPM1 mutation and fusion genes (NUP98/HOXA9 and PRDM16/SKI, respectively). The FLT3-ITD patient with NUP98/HOXA9 and NPM1 achieved CR after IA regimen and obtained continuous CR after HSCT. However, the other FLT3-ITD patient with PRDM16/SKI and NPM1 was refractory to induction ...
Similar publications
As more clinically-relevant genomic features of myeloid malignancies are revealed, it has become clear that targeted clinical genetic testing is inadequate for risk stratification. Here, we develop and validate a clinical transcriptome-based assay for stratification of acute myeloid leukemia (AML). Comparison of ribonucleic acid sequencing (RNA-Seq...
Citations
... FLT3-ITD mutation incidence was in concurrence with studies in other countries that reported the [27][28][29][30] . However, other studies conducted in different countries showed a higher incidence of FLT3-ITD gene mutation among AML patients, with an incidence of 24%, 25.9%, 25%, and 28% in Syrian, Iranian, Turkish, and Chinese patients, respectively 8,[31][32][33] ; this rise in the FLT3-ITD mutation incidence may be due to geographical and ethnic diversities. According to this study, AML patients harboring FLT3-ITD mutation were found to be insignificantly younger than those without the mutation (P = 0.314); this concept was consistent with other previous studies 25,34 . ...
... FLT3 serves as a transmembrane tyrosine kinase receptor involved in cell proliferation. Many APL patients, about 30%-40%, have FLT3 mutation, which is often associated with higher WBC counts and bcr-3 breakpoints of PML gene, but has no effect on survival (3). The key to induction treatment is all-trans retinoic acid (ATRA) combined with arsenic, which helps most patients (90%) achieve complete remission (CR) (4). ...
Background
Acute promyelocytic leukemia (APL) with PML/RARα fusion gene is a distinct variant of acute myeloid leukemia. According to the different break sites of the PML gene, there are three transcripts: Long (bcr1), Variant (bcr2) and Short (bcr3).
Methods
We retrospectively analyzed 82 APL cases with PML-RARα short isoform.
Results
A total of 384 patients with APL were seen, of which 85(22.14%) had PML/RARα short isoform (bcr3) and 82 met the inclusion criteria. The median age was 33.5 years (range, 2-72 years). The incidences of hemorrhage in the intermediate- and high-risk group were higher, but only the incidence between medium and low risk differed statistically (P=0.006), and the incidences of fever, fatigue, splenomegaly, and lymph node enlargement and differentiation syndrome (DS) in those groups were not statistically significant (P>0.05). FLT3 gene mutation rate and the mortality rate of the high-risk group were significantly higher than that of other groups (P=0.040 and P=0.004, P=0.041 and P=0.037, respectively). The mortality rate was lowest (4.26%) in the group treated with ATRA combined with arsenic and anthracycline. The 3-year OS and the 3-year DFS of the low and intermediate-risk group were better (P=0.019 and P=0.017, respectively).
Conclusions
ATRA combined with arsenic and anthracycline had significant impact on outcomes in APL with PML-RARα short isoform.
... Molecular testing is crucial because molecular changes often precede morphological abnormalities. However, clinical molecular testing mainly focuses on gene mutations and fusion genes (3). Recent studies have highlighted the critical roles of transcriptional dysregulation in AML leukemogenesis (4)(5)(6), and genome sequencing might serve as an alternative (7) or complement (8) to traditional testing in the diagnosis and prognosis of the disease. ...
Acute myeloid leukemia (AML) is a clonal hematological malignancy with high mortality rates. The identification of novel markers is urgent for AML. Cytohesins are a subfamily of guanine nucleotide exchange factors activating the ADP-ribosylation factor family GTPases. While the important roles of cytohesins have been reported in various cancers, their function in AML remains unclear. The present study aimed to explore the prognostic impact of cytohesin-4 (CYTH4) and the underlying molecular functions. RNA sequencing and AML clinical data were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases to investigate gene expression and survival. Using the R software, differentially expressed genes were identified between the high- and the low-CYTH4 group. Functional enrichment analysis was conducted by Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analyses. The CIBERSORTx tool was used to explore the proportions of different immune cell types. The molecular function of CYTH4 was also validated in vitro by examining cell growth, cell cycle, apoptosis and colony-forming ability. CYTH4 was significantly upregulated in AML compared with other cancers and normal tissues. High CYTH4 expression was associated with high white blood count (P=0.004) and higher risk status (P<0.001). Patients with high CYTH4 expression had poor overall survival (OS; HR=2.19; 95% CI, 1.40–3.44; P=0.0006; high vs. low) and event-free survival (EFS; HR=2.32; 95% CI, 1.43–3.75; P=0.0006; high vs. low), and these patients could benefit from transplantation (HR=0.29; 95% CI, 0.18–0.47; P<0.0001; transplantation vs. chemotherapy). Multivariate analysis showed that high CYTH4 expression was independently associated with inferior OS (HR=2.49; 95% CI, 1.28–4.83; P=0.007) and EFS (HR=2.56; 95% CI, 1.48–4.42; P=0.001). Functional analysis showed that CYTH4 was involved in immunoregulation. In vitro validation showed knockdown of CYTH4 adversely affected cell growth and induced cell apoptosis, while overexpression of CYTH4 enhanced cell growth. Taken together, CYTH4 is expressed at high levels in AML and can potentially function as a prognostic biomarker.
... Gene fusions are the main molecular markers for prognostic stratification, minimal residual disease (MRD) monitoring, and targeted therapy in patients with AML (12). Furthermore, interactions between gene fusions and mutated genes can play a crucial role in the prognosis and recurrence of AML (13). With an increasing number of new fusions identified, hematopoietic malignancies have been shown to have greater molecular diversity, which may have important implications for sophisticated subtyping with molecular markers. ...
... Studies have indicated that AML with TP53 mutations is often accompanied by complex karyotypes, which is consistent with the findings in our case (35,36). Interactions between fusion and mutated genes can also play a crucial role in the prognosis and recurrence of AML (13). LYN::LINC01900 may affect AML progression by interacting with TP53. ...
Acute myeloid leukemia (AML) is a malignant disease of myeloid hematopoietic stem/progenitor cells characterized by the abnormal proliferation of primitive and naive random cells in the bone marrow and peripheral blood. Acute promyelocytic leukemia (APL) is a type (AML-M3) of AML. Most patients with APL have the characteristic chromosomal translocation t(15; 17)(q22; q12), forming PML::RARA fusion. The occurrence and progression of AML are often accompanied by the emergence of gene fusions such as PML::RARA, CBFβ::MYH11, and RUNX1::RUNX1T1, among others. Gene fusions are the main molecular biological abnormalities in acute leukemia, and all fusion genes act as crucial oncogenic factors in leukemia. Herein, we report the first case of LYN::LINC01900 fusion transcript in AML with a promyelocytic phenotype and TP53 mutation. Further studies should address whether new protein products may result from this fusion, as well as the biological function of these new products in disease occurrence and progression.
... Several factors, including the allelic ratio of the mutation, the presence of co-mutations, and the insertion site, influence the outcome for patients with FLT3-ITD mutation [18]. Isolated FLT3-ITD mutation cannot be responsible for the occurrence of acute myeloblastic leukemia, and it must be associated with other molecular abnormalities: NPM1 mutation, AML1-ETO gene fusion, NUP98 fusion, CBFβ-SMMHC fusion gene, and TET 2 deletion [19]. ...
Acute myeloid leukemia (AML) is a highly aggressive illness distinguished by the accumulation of abnormal hematopoietic precursors in both the bone marrow and peripheral blood. The prevalence of FLT3 gene mutations is high and escalates the probability of relapse and mortality. The survival rates for AML patients, particularly those over 65, are low. FLT3 mutation screening at diagnosis is mandatory, and FLT3 inhibitors are crucial in treating AML patients with mutations. There are two categories of FLT3 mutations: FLT3-ITD located in the juxtamembrane domain and FLT3-TKD in the tyrosine kinase domain. FLT3-ITD is the most common type, affecting nearly a quarter of patients, whereas FLT3-TKD only affects 6–8% of patients. FLT3 inhibitors are now crucial in treating AML patients with FLT3 mutations. When dealing with FLT3-mutated AML, the recommended course of treatment typically involves chemotherapy and midostaurin, followed by allogeneic hematopoietic cell transplantation (HCT) to maximize the likelihood of success. Maintenance therapy can lower the risk of relapse, and gilteritinib is a better option than salvage chemotherapy for relapsed or refractory cases. Clinical trials for new or combined therapies are the most effective approach. This review discusses treatment options for patients with FLT3-mutated AML, including induction chemotherapy and options for relapsed or refractory disease. Additional treatment options may become available as more studies are conducted based on the patient’s condition and susceptibility.
... A recent report indicated that del(13q) is a frequent event in NUP98::KDM5A AML patients, indicating co-occurrence of NUP98-KDMA fusion with RB1 deletion [30]. FLT3-ITD mutation is a recurring event in NUP98::NSD1 positive AML patients [70,84,114]. FLT3-ITD mutation is also observed in some NUP98::HOXA9 AML patients [114,115]. ...
... FLT3-ITD mutation is a recurring event in NUP98::NSD1 positive AML patients [70,84,114]. FLT3-ITD mutation is also observed in some NUP98::HOXA9 AML patients [114,115]. WT1, NRAS, and KRAS mutations frequently co-occur with NUP98::NSD1 and NUP98::HOXA9 [78,116,117]. Patients with NUP98 rearranged AML also have mutations in other genes, such as ASXL1 and MYC [117,118]. ...
Simple Summary: NUP98 rearrangements are frequent events in myeloid malignancies, especially in acute myeloid leukemia (AML). AML patients carrying NUP98 fusions show poor response to standard treatments and adverse outcomes. This review focuses on recent progress in understanding the underlying mechanisms of NUP98 fusion driven leukemias and the development of therapeutics against them. Abstract: NUP98 fusions constitute a small subgroup of AML patients and remain a high-risk AML subtype. There are approximately 30 types of NUP98 fusions identified in AML patients. These patients show resistance to currently available therapies and poor clinical outcomes. NUP98 fusions with different fusion partners have oncogenic transformation potential. This review describes how the NUP98 gene acquires oncogenic properties after rearrangement with multiple partners. In the mechanistic part, the formation of nuclear bodies and dysregulation of the HoxA/Meis1 pathway are highlighted. This review also discusses mutational signatures among NUP98 fusions and their significance in leukemogenesis. It also discusses the clinical implications of NUP98 fusions and their associated mutations in AML patients. Furthermore, it highlights therapeutic vulnerabilities in these leukemias that can be exploited as therapeutic strategies. Lastly, this review discusses the gaps in our knowledge regarding NUP98 fusions in AML, as well as future research opportunities.
... Molecular testing is crucial because molecular changes often precede morphological abnormalities. However, clinical molecular testing mainly focused on gene mutation and fusion genes [3]. ...
Background
Acute myeloid leukemia (AML) is a clonal hematological malignancy with high mortality rates, and the clinical and genomic heterogeneity of AML has complicated therapy development. Identifying novel markers is urgently in need for AML. Cytohesins are a subfamily of guanine nucleotide exchange factors (GEFs) activating ADP-ribosylation factor (ARF) family GTPases. While previous studies have reported the important roles of cytohesins in various cancers, their function in AML remains unclear. Therefore, we performed this study to explore the prognostic impact of cytohesin-4 (CYTH4) and investigate the underlying molecular functions.
Methods
We obtained RNA sequencing data and AML clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets to investigate gene expression and survival. Using R software, we identified differentially expressed genes between the high-CYTH4 group and the low-CYTH4 group. We conducted functional enrichment analysis by performing GO, KEGG, and GSEA analyses. CIBERSORTx tool was used to explore the proportions of different immune cell types. We also evaluated the molecular function of CYTH4 by examining cell growth, cell cycle, apoptosis, and colony-forming ability using CYTH4-knockdown AML cell lines.
Results
CYTH4 was significantly overexpressed in AML when compared with other cancers and normal tissues. High CYTH4 expression was associated with old age (p = 0.014), complex karyotype (p = 0.048), and higher risk status (p = 0.001). Patients with high CYTH4 expression had poor overall survival (OS) (high vs. low, HR = 1.58, 95%CI 1.04–2.45, p = 0.032) and event-free survival (EFS) (high vs. low, HR = 1.84, 95%CI 1.13–2.94, p = 0.013), and these patients could benefit from transplantation (transplantation vs. chemotherapy, HR = 0.35, 95%CI 0.20–0.60, p = 0.0001). Multivariate analysis showed high CYTH4 expression was independently associated with inferior OS (HR = 1.01, 95%CI 1.00-1.03, p = 0.017) and EFS (HR = 1.02, 95%CI 1.00-1.03, p = 0.034). Functional analysis showed that CYTH4 was involved in immunoregulation. In vitro validation showed knockdown of CYTH4 adversely affected cell growth and induced cell apoptosis.
Conclusions
CYTH4 is highly expressed in AML and can potentially function as a prognostic biomarker.
... FLT3-ITD or TKD point mutations are two common types of mutations [23]. In-frame duplications of 3 to 400 bp occur in up to 30% of adult patients with de novo AML [3,24]. ...
Objectives
Acute myeloid leukemia (AML) often presents with abnormal blood cell counts and gene mutations at diagnosis. But, the correlation between blood cell counts and gene mutations and the clinical effects on AML is unclear.
Methods
279 AML patients with FMS-like tyrosine kinase 3(FLT3) mutations were selected. Patients with FLT3 mutations were counted by PCR amplification products direct sequencing and second-generation sequencing (NGS), and blood cell counts at the time of initial diagnosis. The relapse-free survival (RFS) and overall survival (OS) and the influence of the clinical characteristics of patients on the prognosis in different groups were analyzed.
Results
The median of platelet (PLT) count was higher in the TET2 non-mutation group than mutation group and higher in the IDH1/2 mutation group than non-mutation group. The median of white blood cell (WBC) count was reduced in the poor prognosis group. The differences in levels of WBC and PLT count varied among the four groups binding sequence (JM-B), switching sequence (JM-S), zipper sequence (JM-Z), and high chain region (JM-H). The differences in PLT count varied between the insertion length ≥39 bp and <39 bp, and between ≥ 50 bp and <50 bp; The OS and RFS in 10 < WBC (×10⁹/L) < 100 group and in the 30 ≤ PLT (×109/L)<80 group were better.
Conclusions
In AML patients with FLT3 mutations, the location of FLT3 mutations and the type of co-mutated genes may be correlated with blood cell counts, and different blood cell counts may have an impact on the prognosis.
... This type of mutation also induces aberrant activation of FLT3 signaling [14]. The prognostic impact of FLT3-TKD mutations is less clear and these alterations can associate with other mutations and cytogenetic changes [15]. As a consequence of both FLT3-ITD and FLT3-TKD mutations, the intracellular signals mediated by the TK are constitutively translated, thus promoting the cell cycle progression and, in particular, stimulating the transition from G1 to S phase. ...
Uncontrolled proliferative signals and cell cycle dysregulation due to genomic or functional alterations are important drivers of the expansion of undifferentiated blast cells in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells. Therefore, they are largely studied as potential therapeutic targets in the field. We here present the most recent advancements in the evaluation of novel compounds targeting cell cycle proteins or oncogenic mechanisms, including those showing an antiproliferative effect in acute leukemia, independently of the identification of a specific target. Several new kinase inhibitors have been synthesized that showed effectiveness in a nanomolar to micromolar concentration range as inhibitors of FLT3 and its mutant forms, a highly attractive therapeutic target due to its driver role in a significant fraction of AML cases. Moreover, we introduce novel molecules functioning as microtubule-depolymerizing or P53-restoring agents, G-quadruplex-stabilizing molecules and CDK2, CHK1, PI3Kd, STAT5, BRD4 and BRPF1 inhibitors. We here discuss their mechanisms of action, including the downstream intracellular changes induced by in vitro treatment, hematopoietic toxicity, in vivo bio-availability and efficacy in murine xenograft models. The promising activity profile demonstrated by some of these candidates deserves further development towards clinical investigation.
... Several studies demonstrated that DNMT3A mutation was an independent adverse prognostic factor for OS and LFS [12,32,33]. CMML patients with NPM1 and FLT3 mutations tended to have a rapid progress to AML [3,9,28,34], so did TP53 mutation [3,35,36]. The similar findings in our cohort suggested that those genes support a clonal expansion in CMML, as well as leading to a poor prognosis. ...
Background
Chronic myelomonocytic leukemia (CMML) is a rare and heterogeneous hematological malignancy. It has been shown that the molecular abnormalities such as ASXL1 , TET2 , SETBP1 , and SRSF2 mutations are common in Caucasian population.
Methods
We retrospectively analyzed 178 Chinese CMML patients. The targeted next generation sequencing (NGS) was used to evaluate 114 gene variations, and the prognostic factors for OS were determined by COX regression analysis.
Results
The CMML patients showed a unique mutational spectrum, including TET2 (36.5%), NRAS (31.5%), ASXL1 (28.7%), SRSF2 (24.7%), and RUNX1 (21.9%). Of the 102 patients with clonal analysis, the ancestral events preferentially occurred in TET2 (18.5%), splicing factors (16.5%), RAS (14.0%), and ASXL1 (7.8%), and the subclonal genes were mainly ASXL1 , TET2 , and RAS . In addition, the secondary acute myeloid leukemia (sAML) transformed from CMML often had mutations in DNMT3A, ETV6, FLT3 , and NPM1 , while the primary AML (pAML) demonstrated more mutations in CEBPA, DNMT3A, FLT3, IDH1/2, NPM1 , and WT1 . It was of note that a series of clones were emerged during the progression from CMML to AML, including DNMT3A, FLT3 , and NPM1 . By univariate analysis, ASXL1 mutation, intermediate- and high-risk cytogenetic abnormality, CMML-specific prognostic scoring system (CPSS) stratifications (intermediate-2 and high group), and treatment options (best supportive care) predicted for worse OS. Multivariate analysis revealed a similar outcome.
Conclusions
The common mutations in Chinese CMML patients included epigenetic modifiers ( TET2 and ASXL1 ), signaling transduction pathway components ( NRAS ), and splicing factor ( SRSF2 ). The CMML patients with DNMT3A , ETV6 , FLT3 , and NPM1 mutations tended to progress to sAML. ASXL1 mutation and therapeutic modalities were independent prognostic factors for CMML.
