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

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

Im Focus: Hybrid optics bring color imaging using ultrathin metalenses into focus

For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.

But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...

Im Focus: Stem cell divisions in the adult brain seen for the first time

Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.

The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...

Im Focus: Interference as a new method for cooling quantum devices

Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters

Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Researchers invent tiny, light-powered wires to modulate brain's electrical signals

21.02.2018 | Life Sciences

The “Holy Grail” of peptide chemistry: Making peptide active agents available orally

21.02.2018 | Life Sciences

Atomic structure of ultrasound material not what anyone expected

21.02.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>