Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Acute myeloid leukemia : Identification of the genetic alteration responsible for uncontrolled cellular proliferation

20.12.2005


Blood taken from a normal mouse The blue coloring is characteristic of blood cells called blasts, which are proliferating. Blasts are in a small minority. © F. Moreau-Gachelin/Institut Curie


Blood taken from a leukemic mouse In blood taken from a leukemic mouse, the proliferating cells are much more numerous, indicating the presence of leukemic cells. © F. Moreau-Gachelin/Institut Curie


At the Institut Curie, an Inserm team has just identified the molecular mechanism long suspected to account for the formation of malignant cells in the most frequent leukemia – acute myeloid leukemia. For a cell to become leukemic, it must not only proliferate but also no longer become specialized. Mutations in its gene confer autonomous activity on the Kit receptor, thereby allowing cells to proliferate in the absence any external signal.This study was published in the 12 December 2005 issue of Cancer Cell.

Blood cells are produced in the bone marrow from stem cells. In response to growth factors, stem cells differentiate into precursor cells of three blood lines: red blood cells (also called erythrocytes), white blood cells (lymphocytes, macrophages…) and platelets. The cells are only released into the blood when they reach maturity.

Leukemias are malignant blood diseases characterized by the uncontrolled proliferation of blood cells. Lymphoid leukemias, which affect lymphocytes, are distinct from myeloid leukemias, which affect the precursors of all the other blood cell lines. The acute nature of leukemia is reflected in a complete absence of mature cells and in the presence in the bone marrow of numerous cells blocked at an early stage of their maturation.



In France, about 5 000 people are diagnosed with acute leukemia each year. The prognosis varies greatly from one type of leukemia to another. Acute myeloid leukemia accounts for 70% of acute leukemias, without regard to age. Its frequency peaks around 60 years of age. Erythroleukemia(1) is a type of myeloid leukemia.

A two-step mechanism

The molecular mechanisms underlying leukemia are legion and rare exceptions apart there is no single cause. These mechanisms are multi-stage. Murine cancer models used in research, like human tumors, are the result of accumulated genetic anomalies that enable cells to escape the control mechanisms involved in cell differentiation, growth and death by apoptosis.

In the case of erythroleukemia, researchers suspect the existence of a so-called “two-hit” model, although no verification has yet been forthcoming. Erythroleukemia is the consequence of a collaboration between two types of mutations, one that confers a proliferative advantage and one that blocks differentiation.

Uncontrolled proliferation results from mutation of a receptor

Françoise Moreau-Gachelin(2) and her Inserm team at the Institut Curie have now found evidence for this two-step mechanism and have shed light on how it works. They have worked on mice carrying a mutant gene that encodes the transcription factor(3) spi-1/PU.1, whose overexpression is involved in the onset of murine erythroleukemia, which therefore constitutes a good model for the study of human erythroleukemia.

Murine leukemia is characterized by a first event, which blocks the differentiation of precursor cells of the erythrocyte line, and a second event, which induces uncontrolled proliferation of the cells. The mechanism underlying the first event is known to be overexpression of the transcription factor spi-1/PU.1. The mechanism responsible for the second event was until now unknown.

By investigating the sequence of the gene coding for the Kit receptor, Françoise Moreau-Gachelin’s team discovered that this gene was mutated in 86% of the tumors studied.

Acting as a sort of switch, the Kit receptor relays information to the inside of the cell by activating its signaling pathways following receipt of a message from the outside. Françoise Moreau-Gachelin and her colleagues had shown before that some signaling pathways acting downstream of the receptors are “on” in leukemic cells and activate the proliferation of cells in the absence of an order from outside. They have now shown that the mutant Kit receptor is responsible for this uncontrolled activation.

The two-hit model has been validated: for a healthy cell to become malignant, the spi-1/PU.1 gene must be abnormally expressed and the Kit gene must be mutated. Mutation of the Kit gene is therefore a major event responsible for the transformation erythrocyte precursors into malignant cells during acute myeloid leukemia. It is vital to identify all the players in oncogenesis if we are to design new and more effective treatments for the fight against acute myeloid leukemia.

Notes

(1) Erythroleukemia affects red blood cells, also called erythrocytes.

(2) “Leukemogenesis and transcription factor Spi” team in Inserm U 528 “Signal transduction and oncogenesis” headed by Dr Olivier Delattre.

(3) A transcription factor is a protein which controls the expression of a gene.

Catherine Goupillon | alfa
Further information:
http://www.cancercell.org/
http://www.curie.fr

More articles from Life Sciences:

nachricht Making fuel out of thick air
08.12.2017 | DOE/Argonne National Laboratory

nachricht ‘Spying’ on the hidden geometry of complex networks through machine intelligence
08.12.2017 | Technische Universität Dresden

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

Im Focus: Successful Mechanical Testing of Nanowires

With innovative experiments, researchers at the Helmholtz-Zentrums Geesthacht and the Technical University Hamburg unravel why tiny metallic structures are extremely strong

Light-weight and simultaneously strong – porous metallic nanomaterials promise interesting applications as, for instance, for future aeroplanes with enhanced...

Im Focus: Virtual Reality for Bacteria

An interdisciplinary group of researchers interfaced individual bacteria with a computer to build a hybrid bio-digital circuit - Study published in Nature Communications

Scientists at the Institute of Science and Technology Austria (IST Austria) have managed to control the behavior of individual bacteria by connecting them to a...

Im Focus: A space-time sensor for light-matter interactions

Physicists in the Laboratory for Attosecond Physics (run jointly by LMU Munich and the Max Planck Institute for Quantum Optics) have developed an attosecond electron microscope that allows them to visualize the dispersion of light in time and space, and observe the motions of electrons in atoms.

The most basic of all physical interactions in nature is that between light and matter. This interaction takes place in attosecond times (i.e. billionths of a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

Midwife and signpost for photons

11.12.2017 | Physics and Astronomy

How do megacities impact coastal seas? Searching for evidence in Chinese marginal seas

11.12.2017 | Earth Sciences

PhoxTroT: Optical Interconnect Technologies Revolutionized Data Centers and HPC Systems

11.12.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>