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1.
Genes Chromosomes Cancer ; 56(8): 632-638, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28420034

RESUMO

In adult acute myeloid leukemia (AML), the karyotype of the leukemic cell is among the strongest prognostic factors. The Medical Research Council (MRC) and the European LeukemiaNet (ELN) classifications distinguish between favorable, intermediate and adverse cytogenetic risk patients who differ in their treatment response and overall survival. Conventional cytogenetic analyses are a mandatory component of AML diagnostics but they are time-consuming; therefore, therapeutic decisions in elderly patients are often delayed. We investigated whether a screening approach using a panel of seven fluorescence in situ hybridization (FISH) probes would allow rapid identification of adverse chromosomal changes. In a cohort of 334 AML patients, our targeted FISH screening approach identified 80% of adverse risk AML patients with a specificity of 99%. Incorporating FISH screening into diagnostic workup has the potential to accelerate risk stratification and treatment selection, particularly in older patients. This approach may allow therapeutic decisions more quickly, which benefits both patients and physicians and might save costs.


Assuntos
Aberrações Cromossômicas , Análise Citogenética/métodos , Leucemia Promielocítica Aguda/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Cariótipo , Leucemia Promielocítica Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade
2.
Sci Rep ; 6: 28032, 2016 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-27346558

RESUMO

In acute myeloid leukemia (AML), the Fms-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes. Recently, a new and recurrent juxtamembrane deletion mutation (p.Q569Vfs*2) resulting in a truncated receptor was identified. The mutated receptor is expressed on the cell surface and still binds its ligand but loses the ability to activate ERK signaling. FLT3 p.Q569fs-expressing Ba/F3 cells show no proliferation after ligand stimulation. Furthermore, coexpressed with the FLT3 wild-type (WT) receptor, the truncated receptor suppresses stimulation and activation of the WT receptor. Thus, FLT3 p.Q569Vfs*2, to our knowledge, is the first FLT3 mutation with a dominant negative effect on the WT receptor.


Assuntos
Genes Dominantes , Leucemia Mieloide Aguda/genética , Mutação , Tirosina Quinase 3 Semelhante a fms/genética , Linhagem Celular Tumoral , Feminino , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Tirosina Quinase 3 Semelhante a fms/metabolismo
3.
PLoS One ; 10(3): e0120925, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25793878

RESUMO

Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disease with poor outcome. Adequate model systems are required for preclinical studies to improve understanding of AML biology and to develop novel, rational treatment approaches. Xenografts in immunodeficient mice allow performing functional studies on patient-derived AML cells. We have established an improved model system that integrates serial retransplantation of patient-derived xenograft (PDX) cells in mice, genetic manipulation by lentiviral transduction, and essential quality controls by immunophenotyping and targeted resequencing of driver genes. 17/29 samples showed primary engraftment, 10/17 samples could be retransplanted and some of them allowed virtually indefinite serial transplantation. 5/6 samples were successfully transduced using lentiviruses. Neither serial transplantation nor genetic engineering markedly altered sample characteristics analyzed. Transgene expression was stable in PDX AML cells. Example given, recombinant luciferase enabled bioluminescence in vivo imaging and highly sensitive and reliable disease monitoring; imaging visualized minimal disease at 1 PDX cell in 10000 mouse bone marrow cells and facilitated quantifying leukemia initiating cells. We conclude that serial expansion, genetic engineering and imaging represent valuable tools to improve the individualized xenograft mouse model of AML. Prospectively, these advancements enable repetitive, clinically relevant studies on AML biology and preclinical treatment trials on genetically defined and heterogeneous subgroups.


Assuntos
Imageamento Tridimensional/métodos , Leucemia Mieloide Aguda/genética , Medições Luminescentes/métodos , Animais , Modelos Animais de Doenças , Engenharia Genética , Humanos , Camundongos , Mutação/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
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