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Class III Receptor Tyrosine Kinases in Acute Leukemia – Biological Functions and Modern Laboratory Analysis

Acute myeloid leukemia (AML) is a complex disease caused by deregulation of multiple signaling pathways. Mutations in class III receptor tyrosine kinases (RTKs) have been implicated in alteration of cell signals concerning the growth and differentiation of leukemic cells. Point mutations, insertions...

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Autor principal: Berenstein, Rimma
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Libertas Academica 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527365/
https://www.ncbi.nlm.nih.gov/pubmed/26309392
http://dx.doi.org/10.4137/BMI.S22433
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author Berenstein, Rimma
author_facet Berenstein, Rimma
author_sort Berenstein, Rimma
collection PubMed
description Acute myeloid leukemia (AML) is a complex disease caused by deregulation of multiple signaling pathways. Mutations in class III receptor tyrosine kinases (RTKs) have been implicated in alteration of cell signals concerning the growth and differentiation of leukemic cells. Point mutations, insertions, or deletions of RTKs as well as chromosomal translocations induce constitutive activation of the receptor, leading to uncontrolled proliferation of undifferentiated myeloid blasts. Aberrations can occur in all domains of RTKs causing either the ligand-independent activation or mimicking the activated conformation. The World Health Organization recommended including RTK mutations in the AML classification since their detection in routine laboratory diagnostics is a major factor for prognostic stratification of patients. Polymerase chain reaction (PCR)–based methods are well-validated for the detection of fms-related tyrosine kinase 3 (FLT3) mutations and can easily be applied for other RTKs. However, when methodological limitations are reached, accessory techniques can be applied. For a higher resolution and more quantitative approach compared to agarose gel electrophoresis, PCR fragments can be separated by capillary electrophoresis. Furthermore, high-resolution melting and denaturing high-pressure liquid chromatography are reliable presequencing screening methods that reduce the sample amount for Sanger sequencing. Because traditional DNA sequencing is time-consuming, next-generation sequencing (NGS) is an innovative modern possibility to analyze a high amount of samples simultaneously in a short period of time. At present, standardized procedures for NGS are not established, but when this barrier is resolved, it will provide a new platform for rapid and reliable laboratory diagnostic of RTK mutations in patients with AML. In this article, the biological and physiological role of RTK mutations in AML as well as possible laboratory methods for their detection will be reviewed.
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spelling pubmed-45273652015-08-25 Class III Receptor Tyrosine Kinases in Acute Leukemia – Biological Functions and Modern Laboratory Analysis Berenstein, Rimma Biomark Insights Review Acute myeloid leukemia (AML) is a complex disease caused by deregulation of multiple signaling pathways. Mutations in class III receptor tyrosine kinases (RTKs) have been implicated in alteration of cell signals concerning the growth and differentiation of leukemic cells. Point mutations, insertions, or deletions of RTKs as well as chromosomal translocations induce constitutive activation of the receptor, leading to uncontrolled proliferation of undifferentiated myeloid blasts. Aberrations can occur in all domains of RTKs causing either the ligand-independent activation or mimicking the activated conformation. The World Health Organization recommended including RTK mutations in the AML classification since their detection in routine laboratory diagnostics is a major factor for prognostic stratification of patients. Polymerase chain reaction (PCR)–based methods are well-validated for the detection of fms-related tyrosine kinase 3 (FLT3) mutations and can easily be applied for other RTKs. However, when methodological limitations are reached, accessory techniques can be applied. For a higher resolution and more quantitative approach compared to agarose gel electrophoresis, PCR fragments can be separated by capillary electrophoresis. Furthermore, high-resolution melting and denaturing high-pressure liquid chromatography are reliable presequencing screening methods that reduce the sample amount for Sanger sequencing. Because traditional DNA sequencing is time-consuming, next-generation sequencing (NGS) is an innovative modern possibility to analyze a high amount of samples simultaneously in a short period of time. At present, standardized procedures for NGS are not established, but when this barrier is resolved, it will provide a new platform for rapid and reliable laboratory diagnostic of RTK mutations in patients with AML. In this article, the biological and physiological role of RTK mutations in AML as well as possible laboratory methods for their detection will be reviewed. Libertas Academica 2015-08-05 /pmc/articles/PMC4527365/ /pubmed/26309392 http://dx.doi.org/10.4137/BMI.S22433 Text en © 2015 the author(s), publisher and licensee Libertas Academica Ltd. This is an open access article published under the Creative Commons CC-BY-NC 3.0 license.
spellingShingle Review
Berenstein, Rimma
Class III Receptor Tyrosine Kinases in Acute Leukemia – Biological Functions and Modern Laboratory Analysis
title Class III Receptor Tyrosine Kinases in Acute Leukemia – Biological Functions and Modern Laboratory Analysis
title_full Class III Receptor Tyrosine Kinases in Acute Leukemia – Biological Functions and Modern Laboratory Analysis
title_fullStr Class III Receptor Tyrosine Kinases in Acute Leukemia – Biological Functions and Modern Laboratory Analysis
title_full_unstemmed Class III Receptor Tyrosine Kinases in Acute Leukemia – Biological Functions and Modern Laboratory Analysis
title_short Class III Receptor Tyrosine Kinases in Acute Leukemia – Biological Functions and Modern Laboratory Analysis
title_sort class iii receptor tyrosine kinases in acute leukemia – biological functions and modern laboratory analysis
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527365/
https://www.ncbi.nlm.nih.gov/pubmed/26309392
http://dx.doi.org/10.4137/BMI.S22433
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