scholarly journals Mutations within the Activation Loop Domain of FLT3 in Two Pediatric Patients with Refractory Infant Acute Myeloid Leukemia

2020 ◽  
Vol 13 (1) ◽  
pp. 266-270
Author(s):  
Nicole Muhlbauer ◽  
Rebecca E. MacDonell-Yilmaz ◽  
Robyn Borsuk ◽  
Jennifer G. Welch
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Pediatric Patients ◽  
Receptor Gene ◽  
Point Mutations ◽  
Invasive Fungal Disease ◽  
Braf V600e ◽  
Pediatric Aml ◽  
11Q23 Abnormalities ◽  
Acute Myeloid

Approximately 24% of all pediatric acute myeloid leukemia (AML) cases have mutations in the FMS-like tyrosine kinase 3 (FLT3) receptor gene. FLT3-TKD point mutations are rare in pediatrics and often occur in younger patients and in combination with 11q23 abnormalities. There is a paucity of data related to their prognostic implications in children. We describe 2 pediatric patients with FLT3-activating mutations as a feature of their AML. Both were diagnosed in infancy. The first experienced induction failure and had refractory disease without expression of FLT3-TKD mutation on subsequent bone marrow evaluations. His disease also harbored a KMT2A-PICALM gene rearrangement. He died of invasive fungal disease nine months after diagnosis. The second had a post-induction remission but developed swelling of the left calcaneus shown on biopsy to be a myeloid sarcoma positive for a new BRAF V600E mutation in addition to his known KMT2A rearrangement but without FLT3-TKD mutation. Despite multiple courses of therapy including BRAF/MEK-inhibition, he died of progressive disease nine months after diagnosis. FLT3 inhibition was not utilized in either patient as studies have largely focused on its role in internal tandem duplication (ITD) mutations and because the mutation was no longer detectable in either patient on subsequent evaluation. However, these cases add to the suggestion that these mutations confer a worse prognosis in pediatric AML patients.

Most Risk-Stratification Molecular Markers in Acute Myeloid Leukemia (AML) Are Rarely Found in Early Childhood AML in the Middle Eastern Population

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5239-5239
Author(s):  
Hala Abalkhail ◽  
Hassan El-Solh ◽  
Amal Alseraihy ◽  
Asim F Belgaumi ◽  
Abdullah Al-Jefri ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Early Childhood ◽  
Myeloid Leukemia ◽  
Pediatric Patients ◽  
Adult Patients ◽  
Intensive Chemotherapy ◽  
Adult Group ◽  
Molecular Abnormalities ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Abstract 5239 Background: Acute myeloid leukemia (AML) is biologically heterogeneous with significant molecular and clinical variation. Most of the recent studies suggest that AML in pediatric population differs significantly clinically and biologically from adult AML. Numerous newly described molecular abnormalities in AML have been described in adult patients, but except for rare publications, a little is known about the molecular abnormalities and their clinical relevance in pediatric AML, especially in early childhood and when the patients are treated with intensive chemotherapy followed by hematopoietic stem cell transplant (HSCT). The Saudi Arabian population is known to be genetically homogenous due to high consanguinity. Higher incidence of inherited diseases including certain types of cancer has been reported in Saudi Arabia. We attempted to compare the molecular abnormalities and their clinical relevance in pediatric AML patients from Saudi Arabia with adult AML from the same population. Methods: Samples from 87 adult patients with AML and samples from 40 pediatric AML patients were analyzed for FLT3-ITD and FLT3-D835, IDH1, IDH2, NPM1, and DNMT3A mutations by direct sequencing and by fragment length analysis (FLT3 and NPM1). The prevalence of mutations was compared between the adult and pediatric groups. They included patients with intermediate-risk cytogenetics (N=66 adults, N=26 pediatrics) and adverse cytogenetics (N=21 adults, N=14 pediatrics). The median age of the pediatric patients is 7 years, with a range from less than one year to 14 years. All patients were treated with intensive chemotherapy, followed by HSCT in first remission. Results: FLT3-ITD mutation was detected in 18 patients (21%) of the adult group, but detected only in 3 patients of the pediatric group (7.5%). Two of the 3 patients in the pediatric group carrying the FLT3 mutation died within the first year after the transplant. The FLT3-D835 mutation was detected in 6 patients (7%) of the adult group, while none of the pediatric patients showed this mutation. In addition, the pediatric patients showed no mutations in IDH1 or IDH2, while the adult patients showed IDH1 and IDH2 mutations in 6 (7%) and 7 (8%), respectively. Mutations in the DNMT3A gene were detected in three patients (3%) in the adult group, but were not detected in any of the pediatric AML. NPM1 mutations were detected in 9 (10%) of the adult AML patients, but none of the pediatric patients showed NPM1 mutation. Conclusion: This data suggests that the biology of AML in pediatric patients is significantly different from that in the adult patients. Mutations in FLT3, IDH1, IDH2, NPM1, and DNMT3A genes are very rare in pediatric patients. However, our data involves early childhood (90% younger than 13 years of age) and there is a possibility that older children may have higher incidence of mutations. Most of the currently used molecular markers in risk-stratifying adult AML patients are difficult to use in stratifying pediatric AML patients. Disclosures: No relevant conflicts of interest to declare.

Low Frequency and Poor Prognosis Of MLL-Partial Tandem Duplications In Pediatric Acute Myeloid Leukemia Using MLPA Method: The Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1374-1374
Author(s):  
Kentaro Ohki ◽  
Myoung-ja Park ◽  
Hitoshi Sano ◽  
Yusuke Hara ◽  
Norio Shiba ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Pediatric Patients ◽  
Low Frequency ◽  
Rt Pcr ◽  
Mll Gene ◽  
Pediatric Aml ◽  
Tandem Duplications ◽  
Acute Myeloid

Abstract Background Mixed-lineage leukemia (MLL)-partial tandem duplications (PTDs) are found in 3-5% of adult acute myeloid leukemia (AML), and are associated with poor prognosis. Report of the incidence and prognostic relevance of MLL-PTD in pediatric AML is limited and large differences in the frequency have been reported. In pediatric AML cases, a frequency of 10-13% for MLL-PTD was detected using mRNA RT-PCR, whereas a frequency of only 2.5% was detected using multiplex ligation-dependent probe amplification (MLPA). We studied the frequency and prognostic effect of MLL-PTD in pediatric patients with AML treated with JPLSG AML-05 trial (between 2006-2010). Methods MLL-PTD of 331 pediatric de novo AML in the AML-05 trial was analyzed from genomic DNA extracted from their diagnostic bone marrow samples using MLPA analysis. We designed a probe mix for MLPA analysis containing adjacent probes within exon 2-5 and exon 7-13 of the MLL gene for the detection of common and rare type MLL-PTD. Exon 17 of the MLL gene was used as an internal control. We also performed RT-PCR to detect MLL-PTD transcripts to allow comparison with the MLPA results. To assess whether MLL-PTD overlap with known gene abnormalities, such as FLT3, KIT, and NPM1 mutations, mutational analyses of these genes were also performed in patients in the AML-05 trial. Results MLL-PTD was detected in 9 (2.7%) of 331 patients by MLPA analysis. In 303/331 samples mRNA RT-PCR screening for MLL-PTD was performed, and MLL-PTD was detected in 38 (12.5%). In 9 cases, both MLPA and mRNA-RT-PCR were positive for MLL-PTD. The characteristics of the 9 patients with MLL-PTD using MLPA analysis were below. None of the patients harbouring an MLL-rearrangement, t(8;21) or inv(16) revealed a MLL-PTD. All MLL-PTD cases were found in patients with normal cytogenetics. FLT3-ITD was present in 4 of 9 patients with MLL-PTD, while none of KIT and NPM1 mutation was detected in MLL-PTD cases. There was a significantly higher frequency of FLT3-ITD in patients with an MLL-PTD than in those without MLL-PTD (p=0.016). Among these 9 patients, 5 patients were classified as FAB-M5a (p=0.0068), and other 4 patients were classified as FAB-M1, M2, M4 and M6a. The age of patients with MLL-PTD was higher than that of patients without MLL-PTD (median 11.8 years (range; 9-15) and 7.4 years (range; 0-17), respectively; p=0.004). Patients with MLL-PTD tend to have higher white blood cell counts (WBC) at initial diagnosis than those without MLL-PTD (median WBC 6.0×10*9/l (range; 1500-151000) versus 2.2×10*9/l (range; 617-985000a) respectively; p=0.18). All 9 patients with MLL-PTD had events. There was a significantly higher frequency of event including refractory disease, relapse and death in patients with an MLL-PTD than in those without MLL-PTD (p=0.001). Only one of 9 patients was achieved complete remission (CR) after induction therapy (p= 1.1×10-11). Six of 9 patients relapsed, and 5 patients died. Conclusion Using DNA-MLPA as a novel screenings technique, low frequency of MLL-PTD in pediatric AML was found. However, MLL-PTD is highly associated with a poor prognosis in pediatric AML. These data suggest that screening for MLL-PTD in pediatric patients with AML is critical not only for outcome prediction but also for risk-adapted therapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Pediatric acute myeloid leukemia with t(8;21) variant: what is the value on clinical outcome?

2017 ◽  
Vol 4 (5) ◽  
pp. 1890
Author(s):  
Juliana C. Abreu ◽  
Raissa M. Fontes ◽  
Jesamar C. Matos ◽  
Fátima G. Jorge ◽  
Diego S. Lima
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Pediatric Patients ◽  
Clonal Expansion ◽  
Pediatric Acute Myeloid Leukemia ◽  
Favorable Prognosis ◽  
Structural Abnormalities ◽  
Pediatric Aml ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is characterized by clonal expansion of undifferentiated myeloid precursors that results in the bone marrow (BM) failure. Some cytogenetic alterations can be used to predict the prognosis of the disease. AML with t(8;21), presenting RUNX1/RUNX1T1 gene fusion, is associated to favorable prognosis and it is one of most prevalent structural abnormalities in pediatric AML. Variants of t(8;21) has been described, though the prognostic value of these changes remains controversial, especially in pediatric patients. Thereby, we report a pediatric patient with AML with RUNX1/RUNX1T1 fusion presenting the variant t(1;21;8). The diagnosis was confirmed by myelogram, immunophenotyping, cytogenetics and molecular biology. After the diagnosis, the patient was subjected to chemotherapy and submitted to related allogeneic BM transplant. Until this date, the patient has no clinical complaints, predicting a favorable outcome. The register of variants and its proper follow up contributes to a better understanding of the mechanisms involved in these rearrangements and provides information that may be relevant for an appropriate classification and risk stratification of these patients.

Long noncoding RNA GAS6 antisense RNA1 silencing attenuates the tumorigenesis of acute myeloid leukemia cells through targeting microRNA-370-3p/Tetraspanin3 axis

2021 ◽  
pp. 1-13
Author(s):  
Weijuan Lei ◽  
Juliar Lin ◽  
Fang Liu ◽  
Nina Chen
Keyword(s):  
Acute Myeloid Leukemia ◽  
Protein Expression ◽  
Long Noncoding Rna ◽  
Myeloid Leukemia ◽  
Noncoding Rna ◽  
Pediatric Patients ◽  
Migration And Invasion ◽  
Pediatric Aml ◽  
Acute Myeloid

PURPOSE: Acute myeloid leukemia (AML) is a type of hematologic malignancy. This study was attempt to explore the effect of long noncoding RNA GAS6 antisense RNA1 (GAS6-AS1) on pediatric AML and the regulation mechanisms. METHODS: GAS6-AS1, microRNA-370-3p (miR-370-3p), and Tetraspanin3 (TSPAN3) expression in bone marrow (BM) tissues and cells was determined by qRT-PCR. The correlation between GAS6-AS1 and clinicopathological features of pediatric patients with AML was assessed. In vitro, viability and migration and invasion of AML cells were evaluated via MTT and transwell assays, respectively. Interactions among GAS6-AS1, miR-370-3p, and TSPAN3 were revealed by dual-luciferase reporter assays. Western blot was applied to confirm the protein expression of TSPAN3. RESULTS: GAS6-AS1 and TSPAN3 expression was elevated in BM tissues of pediatric patients with AML and AML cells, but miR-370-3p expression was reduced. GAS6-AS1 expression was positively related to French-American-British (FAB) classification in pediatric patients with AML. In vitro, GAS6-AS1 deficiency restrained the viability, migration, and invasion of AML cells. Additionally, GAS6-AS1 mediated miR-370-3p expression indeed and TSPAN3 was identified as a target of miR-370-3p. Furthermore, miR-370-3p overexpression repressed the protein expression of TSPAN3. The feedback experiments demonstrated that miR-370-3p inhibition or TSPAN3 overexpression mitigated the suppressive effect of sh-GAS6-AS1 on the tumorigenesis of AML cells. CONCLUSION: GAS6-AS1 silencing restrained AML cell viability, migration, and invasion by targeting miR-370-3p/TSPAN3 axis, affording a novel therapeutic target for pediatric AML.

scholarly journals Genomic characterization of relapsed acute myeloid leukemia reveals novel putative therapeutic targets

2021 ◽  
Vol 5 (3) ◽  
pp. 900-912
Author(s):  
Svea Stratmann ◽  
Sara A. Yones ◽  
Markus Mayrhofer ◽  
Nina Norgren ◽  
Aron Skaftason ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Pediatric Patients ◽  
De Novo ◽  
Low Frequency ◽  
Whole Genome ◽  
Recurrent Mutations ◽  
De Novo Aml ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Relapse is the leading cause of death of adult and pediatric patients with acute myeloid leukemia (AML). Numerous studies have helped to elucidate the complex mutational landscape at diagnosis of AML, leading to improved risk stratification and new therapeutic options. However, multi–whole-genome studies of adult and pediatric AML at relapse are necessary for further advances. To this end, we performed whole-genome and whole-exome sequencing analyses of longitudinal diagnosis, relapse, and/or primary resistant specimens from 48 adult and 25 pediatric patients with AML. We identified mutations recurrently gained at relapse in ARID1A and CSF1R, both of which represent potentially actionable therapeutic alternatives. Further, we report specific differences in the mutational spectrum between adult vs pediatric relapsed AML, with MGA and H3F3A p.Lys28Met mutations recurrently found at relapse in adults, whereas internal tandem duplications in UBTF were identified solely in children. Finally, our study revealed recurrent mutations in IKZF1, KANSL1, and NIPBL at relapse. All of the mentioned genes have either never been reported at diagnosis in de novo AML or have been reported at low frequency, suggesting important roles for these alterations predominantly in disease progression and/or resistance to therapy. Our findings shed further light on the complexity of relapsed AML and identified previously unappreciated alterations that may lead to improved outcomes through personalized medicine.

scholarly journals High EVI1 Expression Predicts Adverse Outcomes in Children With De Novo Acute Myeloid Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Yongzhi Zheng ◽  
Yan Huang ◽  
Shaohua Le ◽  
Hao Zheng ◽  
Xueling Hua ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Regression Analysis ◽  
Myeloid Leukemia ◽  
Pediatric Patients ◽  
Cox Regression ◽  
De Novo ◽  
Adverse Outcomes ◽  
Cox Regression Analysis ◽  
Pediatric Aml ◽  
Acute Myeloid

BackgroundA high ecotropic viral integration site 1 (EVI1) expression (EVI1high) is an independent prognostic factor in adult acute myeloid leukemia (AML). However, little is known of the prognostic value of EVI1high in pediatric AML. This study aimed to examine the biological and prognostic significance of EVI1high in uniformly treated pediatric patients with AML from a large cohort of seven centers in China.MethodsA diagnostic assay was developed to determine the relative EVI1 expression using a single real-time quantitative polymerase chain reaction in 421 newly diagnosed pediatric AML patients younger than 14 years from seven centers in southern China. All patients were treated with a uniform protocol, but only 383 patients were evaluated for their treatment response. The survival data were included in the subsequent analysis (n = 35 for EVI1high, n = 348 for EVI1low).ResultsEVI1high was found in 9.0% of all 421 pediatric patients with de novo AML. EVI1high was predominantly found in acute megakaryoblastic leukemia (FAB M7), MLL rearrangements, and unfavorable cytogenetic aberrance, whereas it was mutually exclusive with t (8; 21), inv (16)/t (16; 16), CEBPA, NPM1, or C-KIT mutations. In the univariate Cox regression analysis, EVI1high had a significantly adverse 5-year event-free survival (EFS) and overall survival (OS) [hazard ratio (HR) = 1.821 and 2.401, p = 0.036 and 0.005, respectively]. In the multivariate Cox regression analysis, EVI1high was an independent prognostic factor for the OS (HR = 2.447, p = 0.015) but not EFS (HR = 1.556, p = 0.174). Furthermore, EVI1high was an independent adverse predictor of the OS and EFS of patients with MLL rearrangements (univariate analysis: HR = 9.921 and 7.253, both p < 0.001; multivariate analysis: HR = 7.186 and 7.315, p = 0.005 and 0.001, respectively). Hematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) provided EVI1high patients with a tendential survival benefit when compared with chemotherapy as a consolidation (5-year EFS: 68.4% vs. 50.8%, p = 0.26; 5-year OS: 65.9% vs. 54.8%, p = 0.45).ConclusionIt could be concluded that EVI1high can be detected in approximately 10% of pediatric AML cases. It is predominantly present in unfavorable cytogenetic subtypes and predicts adverse outcomes. Whether pediatric patients with EVI1high AML can benefit from HSCT in CR1 needs to be researched further.

scholarly journals Treatment adherence and abandonment in acute myeloid leukemia in pediatric patients at a low-resource cancer center in India

2019 ◽  
Vol 40 (4) ◽  
pp. 501
Author(s):  
Mikael Segerlantz ◽  
Sudha Sinha ◽  
Gustav Brattström ◽  
Gayatri Palat ◽  
Vineela Rapelli ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Treatment Adherence ◽  
Myeloid Leukemia ◽  
Pediatric Patients ◽  
Cancer Center ◽  
Low Resource ◽  
Acute Myeloid
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