FLT3–ITD and its current role in acute myeloid leukaemia

Lagunas‐Rangel, Francisco Alejandro; Chávez‐Valencia, Venice

doi:10.1007/s12032-017-0970-x

Cited by 87 publications

(71 citation statements)

References 123 publications

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“…This result is nearly identical with the data presented by Sebastian Scholl . FLT3 ‐ITD mutations were reported as the second most frequent molecular aberration in AML . Here we found 19.8% cases with FLT3 ‐ITD positive.…”

Section: Discussionsupporting

confidence: 48%

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Prognostic utility of six mutated genes for older patients with acute myeloid leukemia

Wang

et al. 2017

Intl Journal of Cancer

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Approximately 50% of older patients with acute myeloid leukemia (AML) do not obtain chromosomal abnormalities as an effective risk-stratification, and present cytogenetically normal AML (CN-AML). To develop a reliable prediction model for stratifying the risk of these elderly patients, we conducted a study with a discovery and validation design. As a result, we found the top 6 mutated genes in the discovery cohort of 26 case by the whole exome sequencing, and verified as recurrent mutations in the large cohort of 329 patients by Sanger sequencing. The top 6 genes were NPM1, FLT3-ITD, DNMT3A, CEBPA double allele, IDH1 and IDH2 mutations, and the frequency of each gene in the combining cohort was 36.8%, 19.8%, 20.1%, 5.8%, 14.9% and 22.5%, respectively. In addition, clinical variables such as age, white blood cell counts, genes of IDH1 and DNMT3A mutations, European LeukemiaNet genotype (NPM1 mutations and lacking FLT3-ITD or CEBPA double allele mutations) and treatment protocols were independent factors for predicting the probabilities of overall and event-free survival. The prediction nomograms based on these significant factors showed accurate discrimination. In conclusion, we developed a reliable prediction model for stratifying the risk of elderly patients with CN-AML.

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Section: Discussionsupporting

confidence: 48%

“…16 FLT3-ITD mutations were reported as the second most frequent molecular aberration in AML. 17 Here we found 19.8% cases with FLT3-ITD positive. The incidence of 5.8% CEBPA in our patients was similar to the 4% incidence reported in recent studies of older patients with intermediate risk cytogenetics.…”

Section: Tumor Markers and Signaturesmentioning

confidence: 50%

Prognostic utility of six mutated genes for older patients with acute myeloid leukemia

Wang

et al. 2017

Intl Journal of Cancer

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“…FLT3 -ITD mutation induces constitutive receptor activation, ligand independent dimerization and autophosphorylation which supports uncontrolled leukemic cells proliferation and apoptosis. The leukemic cells burden is the resultant of uncontrolled proliferation and apoptotic-antiapoptotic activity ( 4 , 21 ). In this study, we examined cyclin D1 as a cell proliferation marker and Bcl-xL as an anti-apoptosis activity marker of leukemic cells ( 22 , 23 ).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has been proposed that AML prognosis and risk stratification was determined based on the cytogenetic and molecular findings. The findings in favorable risk cases include inv16, t (16,16), t (8,21), t (15,17), normal cytogenetics with CEBPA biallelic gene mutation and NPM1 gene mutation without FLT3-ITD mutation. Findings in intermediate risk cases include normal cytogenetics, +8 and t (9,11) and the findings in poor risk cases include complex cytogenetic abnormalities (>3 abnormalities), -5/5q-, -7, 7q-and 11q23 rearrangement except t (9,11), inv(3) or t (3,3), t (6,9), t (9,22) and normal cytogenetics with FLT3-ITD gene mutation (2).…”

Section: Introductionmentioning

confidence: 99%

The Association of FLT3-ITD Gene Mutation with Bone Marrow Blast Cell Count, CD34, Cyclin D1, Bcl-xL and hENT1 Expression in Acute Myeloid Leukemia Patients

et al. 2020

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Scan to discover online Background & Objective: FLT3-ITD has been recently used as a molecular prognostic marker for risk classification in acute myeloid leukemia (AML) therapy. In this study we aimed to investigate the association of FLT3-ITD gene mutation with bone marrow blast cell count, CD34 expression as malignant cell burden, cyclin D1 and Bcl-xL expressions as indexes of cell proliferation and anti-apoptosis and human equilibrative nucleoside transporter 1 (hENT1) expression as cytarabine transporter during AML treatment. Methods: We investigated FLT3-ITD mutations, bone marrow blast cell count, CD34, cyclin D1, Bcl-xL and hENT1 expression in bone marrow aspirates from 22 de novo AML patients in a cross sectional study. Results: FLT3-ITD mutations were observed in 5 out of 22 de novo AML patients (22.7%). Patient with FLT3-ITD mutations had higher blast cell counts (79.5% vs 56.1%, P=0.004). In patients with FLT3-ITD mutations, CD34 and cyclin D1 expressions were higher (MFI 328.80 vs 25.78, P=0.003 and MFI 74.51 vs 57.15 P=0.005) than the patients without mutations. hENT1 expression in AML with FLT3-ITD mutation was lower (MFI 29.64 versus 56.32, P=0.0000) than in mutation-free AML. There was no significant difference in Bcl-xL expression between patients with and without mutations (P=0.61). Conclusion: A significant association was found between FLT3-ITD gene mutations in AML patients with bone marrow blast cell count, CD34, cyclin D1 and hENT1 expressions, however no association was obtained with Bcl-xL expression. These findings support the role of such mutation in pathogenesis of AMLand its contribution in rearrangement of standard therapy with cytarabine in management of AML.

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“…Both types of mutations promote ligand-independent auto-phosphorylation and constitutive activation of the receptor. This unregulated activation impairs normal hematopoiesis and contributes to leukemogenesis (5).…”

Section: Introductionmentioning

confidence: 99%

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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FLT3–ITD and its current role in acute myeloid leukaemia

Cited by 87 publications

References 123 publications

Prognostic utility of six mutated genes for older patients with acute myeloid leukemia

Prognostic utility of six mutated genes for older patients with acute myeloid leukemia

The Association of FLT3-ITD Gene Mutation with Bone Marrow Blast Cell Count, CD34, Cyclin D1, Bcl-xL and hENT1 Expression in Acute Myeloid Leukemia Patients

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

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