Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Defect in Ikaros gene mimics human B cell leukemia

10.02.2014
Meinrad Busslinger and his team from the Institute of Molecular Pathology (IMP) investigate the differentiation of stem cells to mature B cells.

They now present for the first time molecular details on the role of the Ikaros gene during early B cell development. A defect in Ikaros function causes an early block in B-lymphopoiesis and prevents the development of mature B cells.


Cross-section through the bone marrow of a mouse lacking the Ikaros Protein

The cells stay in an aberrant state, which closely resembles that of cells in B-ALL, a special form of human B cell leukemia. The results of this study are published in the current Advance Online edition of Nature Immunology (doi; 10.1038/ni.2828).

The immune system consists of a complex structure of organs, cell types and cell-cell interactions which protects the organism from harmful intruders as well as aberrant cells within the body. Two mechanisms of immunological defense can be distinguished – innate and adaptive immunity. Cells from the adaptive immune system recognize specific structures of invaders and develop defense mechanisms accordingly. B and T cells from the group of white blood cells represent the main players of the adaptive immune defense.

Role of Ikaros in B cells is no longer a myth

B cells are derived from blood stem cells in the bone marrow. By differentiating through several stages of lymphopoiesis, these stem cells give rise to fully functional, mature B cells. This process is tightly controlled by a group of regulatory proteins called transcription factors. “We already know several transcription factors that play a central role in B cell differentiation. Pax5 for example represents a critical factor which activates the B cell-specific program in precursor cells and simultaneously suppresses alternative cell fates”, Busslinger explains. ”For Ikaros we did not know until now what this factor is doing during early B cell development”.

The researchers from Busslinger’s team therefore analyzed mice specifically lacking Ikaros from an early stage of B cell development on. They found that Ikaros deficiency arrested B cell development in an aberrant “pro-B” cell stage and prevented further differentiation. Without Ikaros, the cells were not able to transmit certain signals via their cell surface receptors. Furthermore, they showed increased cell adhesion and reduced migration compared to normal cells.

European grant allows comprehensive analyses

In 2011, Busslinger was awarded one of the prestigious „ERC Advanced Grants“ from the European Union. This generous financial support made it possible to tackle a large scope project - the systematic analysis of transcription factors in the immune system. Busslinger and his team use the technology of biotin-tagging to add a “molecular label” to transcription factors for their studies. This facilitates the isolation of these proteins from murine B cells. Despite the huge effort that comes with this method, Busslinger and his co-workers have already labelled and analysed about ten transcription factors using biotin-tagging. In most cases, they were successful with this approach. For Ikaros, this meant gaining fundamental new insights into the molecular way of action. The researchers identified a large number of genes that are controlled by this transcription factor during early B cell development.

Striking similarity to human tumor cells

The Ikaros gene is a so-called tumor-suppressor gene that protects cells from becoming tumorigenic under normal conditions. Loss of the function of this gene has been associated with the development of “B-ALL”, a certain form of human leukemia, which requires further genetic alterations in addition to the Ikaros gene mutation. As in mice with a mutated Ikaros gene, B cells from human B-ALL patients are arrested at an early checkpoint of B cell development.

Due to the striking similarity between the defect in the mouse model and human cancers, this study may help to understand how leukemia develops at the molecular level. In the future, the findings might be valuable in devising new concepts for the prevention or therapy of blood cancer.

Original Publication

TA Schwickert, H. Tagoh, S. Gültekin, A. Dakic, E. Axelsson, M. Minnich, A. Ebert, B. Werner, M. Roth, L. Cimmino, RA Dickins, J. Zuber, M. Jaritz and M. Busslinger. „Stage-specific control of early B cell development by the transcription factor Ikaros”, Nature Immunology 15, doi; 10.1038/ni.2828.

This work was funded by Boehringer Ingelheim, an ERC Grant from the EU, the Austrian Initiative GEN-AU of the Federal Ministry of Science and Research and an EMBO grant.

Illustration

An illustration can be downloaded from the IMP Website and used free of charge in connection with this press release: http://www.imp.ac.at/pressefoto-Ikaros

Caption: Cross-section through the bone marrow of a mouse lacking the Ikaros protein. In the absence of Ikaros, an important early checkpoint of B-lymphopoiesis is no longer functional. As a consequence, early B cell development is arrested at an aberrant “pro-B” cell stage. Staining of the sections visualizes the arrested pro-B cells (green), myeloid cells (red) and nuclei (blue). Copyright: IMP

About Meinrad Busslinger

Meinrad Busslinger was born in Switzerland in 1952. He studied Biochemistry at the ETH Zürich and obtained a doctorate in molecular biology from the University of Zürich. Following postdoctoral studies at the MRC Institute Mill Hill, London, he became a group leader at the University of Zürich. In 1987, he followed Max Birnstiel as a Senior Group Leader to the newly founded IMP in Vienna. Busslinger is Director of Academic Affairs at the IMP, and since 2013 also scientific Deputy Director of the institute.

Busslinger is Professor at the University of Vienna and a full member of the Austrian Academy of Sciences and of the European Molecular Biology Organisation. He has published over 160 papers in peer-reviewed journals and serves on editorial boards of several scientific journals. Busslinger was awarded the Wittgenstein prize of the Austrian Government in 2001 and the Virchow Medal by the University of Würzburg in 2010.

About the IMP

The Research Institute of Molecular Pathology (IMP) in Vienna is a basic biomedical research institute largely sponsored by Boehringer Ingelheim. With over 200 scientists from 30 nations, the IMP is committed to scientific discovery of fundamental molecular and cellular mechanisms underlying complex biological phenomena. Research areas include cell and molecular biology, neurobiology, disease mechanisms and computational biology.

Contact

Dr. Heidemarie Hurtl
Communications
IMP Research Institute of Molecular Pathology
Dr. Bohr-Gasse 7
A 1030 Vienna
Tel. +43 (0)1 79730-3625
E-mail: hurtl@imp.ac.at

Dr. Heidemarie Hurtl | idw
Further information:
http://www.imp.ac.at

More articles from Life Sciences:

nachricht Quasi-sexual gene transfer drives genetic diversity of hot spring bacteria
29.05.2015 | Carnegie Institution

nachricht Scientists use unmanned aerial vehicle to study gray whales from above
29.05.2015 | NOAA National Marine Fisheries Service

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Lasers are the key to mastering challenges in lightweight construction

Many joining and cutting processes are possible only with lasers. New technologies make it possible to manufacture metal components with hollow structures that are significantly lighter and yet just as stable as solid components. In addition, lasers can be used to combine various lightweight construction materials and steels with each other. The Fraunhofer Institute for Laser Technology ILT in Aachen is presenting a range of such solutions at the LASER World of Photonics trade fair from June 22 to 25, 2015 in Munich, Germany, (Hall A3, Stand 121).

Lightweight construction materials are popular: aluminum is used in the bodywork of cars, for example, and aircraft fuselages already consist in large part of...

Im Focus: Solid-state photonics goes extreme ultraviolet

Using ultrashort laser pulses, scientists in Max Planck Institute of Quantum Optics have demonstrated the emission of extreme ultraviolet radiation from thin dielectric films and have investigated the underlying mechanisms.

In 1961, only shortly after the invention of the first laser, scientists exposed silicon dioxide crystals (also known as quartz) to an intense ruby laser to...

Im Focus: Advance in regenerative medicine

The only professorship in Germany to date, one master's programme, one laboratory with worldwide unique equipment and the corresponding research results: The University of Würzburg is leading in the field of biofabrication.

Paul Dalton is presently the only professor of biofabrication in Germany. About a year ago, the Australian researcher relocated to the Würzburg department for...

Im Focus: Basel Physicists Develop Efficient Method of Signal Transmission from Nanocomponents

Physicists have developed an innovative method that could enable the efficient use of nanocomponents in electronic circuits. To achieve this, they have developed a layout in which a nanocomponent is connected to two electrical conductors, which uncouple the electrical signal in a highly efficient manner. The scientists at the Department of Physics and the Swiss Nanoscience Institute at the University of Basel have published their results in the scientific journal “Nature Communications” together with their colleagues from ETH Zurich.

Electronic components are becoming smaller and smaller. Components measuring just a few nanometers – the size of around ten atoms – are already being produced...

Im Focus: IoT-based Advanced Automobile Parking Navigation System

Development and implementation of an advanced automobile parking navigation platform for parking services

To fulfill the requirements of the industry, PolyU researchers developed the Advanced Automobile Parking Navigation Platform, which includes smart devices,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International symposium: trends in spatial analysis and modelling for a more sustainable land use

20.05.2015 | Event News

15th conference of the International Association of Colloid and Interface Scientists

18.05.2015 | Event News

EHFG 2015: Securing health in Europe. Balancing priorities, sharing responsibilities

12.05.2015 | Event News

 
Latest News

Quasi-sexual gene transfer drives genetic diversity of hot spring bacteria

29.05.2015 | Life Sciences

First Eastern Pacific tropical depression runs ahead of dawn

29.05.2015 | Earth Sciences

Donuts, math, and superdense teleportation of quantum information

29.05.2015 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>