Molecular Characterization of Pediatric Acute Myeloid Leukemia: Results of a Multicentric Study in Brazil

Andrade, Francianne Gomes; Noronha, Elda Pereira; Brisson, Gisele Dallapicola; Bueno, Filipe dos Santos Vicente; Cezar, Ingrid Sardou; Terra-Granado, Eugênia; Thuler, Luiz Cláudio Santos; Pombo‐de‐Oliveira, Maria S.; Arancibia, Alejandro Mauricio; Basegio, Rosania; Brito, Patricia Carneiro de; Carvalho, Eny; Córdoba, José Carlos; Costa, Imaruí; Cóser, Virgínia Maria; Deyl, Adriana Vanessa Santini; Dias, Anna Carolina Silva; Fialho, Eloisa Cartaxo; Freire, Bruno Marcelo Rocha; Gurgel, Renata Silva de Carvalho; Ikoma, Maura Rosane Valério; Köster, Ingrid; Magalhães, Isis Maria Quezado; Marinho, Ana Maria; Melaragno, Renato; Moura, Suellen Valadares; Neves, Gustavo Ribeiro; Oliveira, Claudia; Renault, Ilana Zalcberg; Salles, Terezinha de Jesus Marques; Silva, Denise Browsfield; Souza, Marcelo Santos de; Vieira, Tállita Meciany Farias; Werneck, Fernando de Almeida; Winn, Ana Freund; Zamperlini, Gustavo

doi:10.1016/j.arcmed.2016.11.015

Cited by 21 publications

(16 citation statements)

References 40 publications

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“…Although the frequency of FLT3 mutation was higher in the female group, no statistically significant difference in gender distribution was observed, similar to what has been found in most series (18). No association was seen between age at diagnosis, WBC, or blast percentage at bone marrow and the presence of FLT3 mutations.…”

Section: Discussionsupporting

confidence: 85%

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Profiling FLT3 Mutations in Mexican Acute Myeloid Leukemia Pediatric Patients: Impact on Overall Survival

et al. 2020

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Background: Acute myeloid leukemia (AML) is the second most frequent leukemia in childhood. The FLT3 gene participates in hematopoietic stem cell proliferation. FLT3 mutations are recurrent in AML and influence prognosis. In Mexican pediatric AML patients, FLT3 mutational profile, and their clinical impact have not been evaluated. Aim of the study: This study aimed to identify the profile of FLT3 mutations in pediatric patients with de novo AML and to assess their possible influence on overall survival (OS) and other clinical features. Methods: Massive parallel target sequencing of FLT3 was performed in 80 patients. Results: FLT3 mutations [internal tandem duplication (ITD) or tyrosine kinase domain (TKD)] were identified in 24% of them. OS was significantly lower in FLT3 POS cases than in FLT3 NEG (p = 0.03). The average OS for FLT3 POS was 1.2 vs. 2.2 years in FLT3 NEG. There were no significant differences in the children's sex, age, percentage of blasts in Molina Garay et al. FLT3 in Mexican AML Pediatric Patients bone marrow aspirate, or white blood cell count in peripheral blood at diagnosis between both groups. No differences were identified stratifying by the mutational load (high > 0.4) or type of mutation. The negative effect of FLT3 mutations was also observed in patients with acute promyelocytic leukemia (APL). Conclusions: FLT3 mutational profile is described in Mexican pediatric AML patients for the first time. Mutated FLT3 negatively impacts the outcome of AML patients, even considering the APL group. The clinical benefit from treatment with tyrosine kinase inhibitors in the FLT3 POS pediatric patients needs to be assessed in clinical trials. FLT3 testing may contribute to better risk stratification in our pediatric AML patients.

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Section: Discussionsupporting

confidence: 85%

“…The reported prevalence in Costa Rica and Argentina is lower than in our patients (14.3% in 14 patients and 15.2% in 92 patients, respectively) (17). The results from Brazil are very similar to those from Mexico, with 23.3% reported in an extensive collaborative analysis, including a large number of pediatric patients (18).…”

Section: Discussionsupporting

confidence: 79%

Profiling FLT3 Mutations in Mexican Acute Myeloid Leukemia Pediatric Patients: Impact on Overall Survival

et al. 2020

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“… 16 Mutations in NPM1 , IDH2 , and biallelic CEBPA are favorable risk factors; 13 while FLT3-ITD positive, IDH1 , TET2 , 13 KRAS , 17 U2AF1 , and PTPN11 are always associated with poor outcomes. 18 , 19 Although showing different mutation rates in AML patients, genes such as NRAS , 20 SMC1A , SMC3 , and RAD21 showed no influence in the prognosis. 21 …”

Section: Discussionmentioning

confidence: 93%

Biological and clinical influences of <em>NPM1 </em>in acute myeloid leukemia patients with <em>DNMT3A</em> mutations

Yang

Shi

Zhang

et al. 2018

CMAR

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PurposeDNMT3A and NPM1 mutations are known to impact the prognosis of acute myeloid leukemia (AML). DNMT3A mutations are negative prognostic factors, while NPM1 mutations are low-risk factors and inclined to concurrently appear with DNMT3A mutations. In this study, we aimed to find out how NPM1 mutations affect patients’ outcomes in the background of DNMT3A mutations.Patients and methodsWe screened The Cancer Genome Atlas (TCGA) database and found 51 AML patients with DNMT3A mutations. Of them, 28 patients had a combination of NPM1 mutations.ResultsIn all, NPM1 had the highest mutation frequency (n=28, 54.9%). DNMT3Amut/NPM1mut patients had higher bone marrow (BM) blasts (P=0.015), higher FLT3-ITD/TKD rate (P=0.004), and lower IDH2 mutation rate (P=0.014) than the DNMT3Amut/NPM1wild patients, while their prognoses were the same as the DNMT3Amut/NPM1wild patients (P>0.1). All 51 patients benefited from hematopoietic stem cell transplantation (HSCT) treatment (P=0.005 and 0.001 for event-free survival [EFS] and overall survival [OS], respectively). In the 23 patients with DNMT3Amut/NPM1wild, those who received HSCT had prolonged EFS and OS (P=0.043 and 0.008, respectively), while HSCT treatment did not produce a positive impact on EFS and OS in the remaining 28 patients with DNMT3Amut/NPM1mut (P=0.056 and 0.053, respectively).ConclusionOur study found that NPM1 mutations influenced BM blasts’ percentage, FLT3-ITD/TKD rate, and IDH2 mutation rate in AML patients with DNMT3A mutations but made little difference to the overall prognosis. While HSCT treatments benefited all DNMT3Amut patients, it was better for DNMT3Amut/NPM1wild patients to extend their EFS and OS.

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“…Cytogenetic research in CN-AML is an increasingly popular field; mutations or the methylation status of some genes has not only been found to predict the prognosis of patients with CN-AML, but also serve as an important target for treatments 31 ; for example, mutations in NPM1, IDH2 and CEBPA genes have been associated with a good prognosis in CN-AM 31 , 32 , whereas FLT3-ITD positive, IDH1, TET2, KRAS, U2AF1 and PTPN11 mutations all predicted a poorer prognosis in AML 33 - 35 . Notably, NRAS, SMC1A, SMC3 and RAD21 mutations have been reported to have no effect on the prognosis of patients with AML 36 , 37 In addition, the methylation of TET2 and FLT3 improved the prognosis of patients with AML 27 .…”

Section: Discussionmentioning

confidence: 99%

Prognostic role of ACTL10 in Cytogenetic Normal Acute Myeloid Leukemia

Lai¹,

Zhang²,

He³

et al. 2020

J. Cancer

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ACTL10 is a member of the actin family; however, despite previous studies suggesting that certain proteins in this family may be related to the pathogenesis of leukemia, to the best of our knowledge, no studies to date have demonstrated any association between ACTAL10 and leukemia. Thus, the present study aimed to determine the association between ACTL10 expression levels, DNA methylation levels and the clinical prognosis in cytogenic normal acute myeloid leukemia (CN-AML). Data from seventy-five patients with CN-AML and patients with AML treated with chemotherapy or allogeneic hematopoietic stem cell transplantation were obtained from The Cancer Genome Atlas (TCGA) dataset and were used to analyze the clinical prognosis of ACTL10 RNA expression levels and DNA methylation levels. In addition, the study also investigated the combined clinical prognosis of ACTL10 RNA expression levels and ACTL10 DNA methylation levels in 74 patients with CN-AML from the TCGA dataset. ACTL10 RNA expression levels were observed to be highly expressed in patients with CD34 + /CD38 + AML (P<0.01). Both ACTL10 RNA expression levels and DNA methylation were found to be independent prognostic factors for patients with CN-AML; patients with CN-AML in the ACTL10 RNA-high expression group had an increased EFS (P=0.0016) and OS (P=0.014) and patients in ACTL10 DNA methylation-low group also demonstrated a long EFS (P<0.0001) and OS (P=0.004). Notably, integrating ACTL10 RNA expression levels and ACTL10 DNA methylation levels could more accurately predict the prognosis of patients with CN-AML (EFS and OS, P<0.0001). In conclusion, the findings of the present study suggested that the high RNA expression levels and low DNA methylation levels of ACTL10 may predict a good prognosis in patients with CN-AML.

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Molecular Characterization of Pediatric Acute Myeloid Leukemia: Results of a Multicentric Study in Brazil

Cited by 21 publications

References 40 publications

Profiling FLT3 Mutations in Mexican Acute Myeloid Leukemia Pediatric Patients: Impact on Overall Survival

Profiling FLT3 Mutations in Mexican Acute Myeloid Leukemia Pediatric Patients: Impact on Overall Survival

Biological and clinical influences of <em>NPM1 </em>in acute myeloid leukemia patients with <em>DNMT3A</em> mutations

Prognostic role of ACTL10 in Cytogenetic Normal Acute Myeloid Leukemia

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