Exploring the Mechanisms of Leukemia

Vienna, 10 June 2007 – A diagnosis of leukemia still strikes terror in the heart of a patient but is not the certain death knell it once was. Many patients can be cured; others can enjoy several additional years of life relatively free of symptoms. Nonetheless, this type of tumor continues to pose a number of unsolved mysteries. Why is the outcome of a treatment still so unpredictable? Why is it that one and the same therapy works perfectly on one patient and not at all on a second, even though the cell changes involved are seemingly identical under a microscope?

The most modern high-tech examination methods, especially molecular biological microarray technology, now allow researchers to watch leukemia in action at a molecular level. The latest findings presented at the Congress of the European Hematology Association (EHA) in Vienna from 7 through 10 June are more than impressive. In their study of leukemia, scientists are unveiling one secret after another of this insidious disease. Leukemia is the general term for malignant diseases of the organ system were blood cells are produced: the bone marrow. A trait all of these diseases have in common is the enormous proliferation of white blood cells and a corresponding suppression of the red blood cells that transport oxygen.

Rendering molecular dysfunctions visible

Dr. Lars Bullinger from the Department of Internal Medicine at the University of Ulm in Germany, an award-winning leukemia researcher and a speaker at the congress: “Until now, we have made a distinction between five main types of leukemia based on cell types and the course of the disease[1], and have also identified a number of sub-types over the years. The new analysis methods now allow us for the first time to decode and observe hereditary material, namely DNA, and the effect it exerts via proteins formed on the basis of the information it contains.” Researchers discovered, for example, that there are a number of different dysfunctions at molecular level that trigger leukemia singly or in a variety of combinations with each other. Dr. Bullinger: “In other words, there are many roads leading to the same destination. That is why certain therapies are effective in one case and not in another. Treatment succeeds if it blocks the exact path the disease is traveling along in the specific case.” Interesting examples from this innovative branch of research were presented at the EHA Congress.

Micro-RNAs refine the diagnosis

Dr. Bullinger himself has been studying what are known as micro-RNAs. They act as switches of sorts and were just recently discovered. About 400 have been identified thus far. “About a third of genes operate in such a way that after their information is read, the appropriate micro-RNAs have to give the okay for the gene-specific protein to be formed,” the genetic expert explained. “We know that cancer is associated with dysfunctions of this post-transscriptural gene regulation.” In their study, the researchers from Ulm created micro-RNA profiles for 91 patients covering all previously known types of acute myelogenous leukemia (AML) and had their computers search for correlations. “We not only detected new subgroups but also a specific micro-RNA signature that indicates acute promyelocytic leukemia,” Dr. Bullinger noted.

Leukemia in children: basis for better therapies

A research group headed by Dr. Silvia Bungaro from the M. Tettamanti Research Center in Monza, Italy, tackled yet another problem: 25% of all children with acute lymphoblastic leukemia (ALL) show none of the chromosomal changes known as markers for this disease. Since chromosomes are only the larger subdivisions of the human genotype, the scientists “zoomed in” with their magnifying glasses and checked out the entire genome for the tiniest mutations, known as single nucleotide polymorphisms or SNPs, and then looked to see which genes were switched on or off. In the process, previously hidden genetic damage was brought to light and new genotype subgroups were distilled for ALL.

Another group of scientists headed by Dr. Benedetta Accordi from the University of Padua concentrated on children’s B-cell ALL. In spite of the great strides forward in therapy in recent decades, about 30 percent of children suffering from this disease fail to respond to any conventional therapy. That means that in these cases, the tumor is obviously using signal transmission mechanisms other than the ones blocked by the usual therapies. Using reverse phase protein arrays, the researchers analyzed which proteins in their young patients’ cancer cells were phosphorylated and which were not. This trait shows whether the cells are currently active or “sleeping.” Their findings: tumors resistant to the cortisone preparation Prednison actually use other information pathways within the cell than tumors against which Prednison is effective. These resistant tumors might therefore respond to a completely different kind of drug, namely kinasis inhibitors.

Genome comparisons point the way to effective therapy approaches

Perhaps the biggest effort worldwide to uncover the fundamental traits of leukemia relevant to therapy is the MILE Study (MILE = MIcroarrays in LEucemia), in which hospitals and laboratories on four continents are participating. The goal is to use microarray analyses to analyze the complete genome (DNA, hereditary material) of countless leukemia patients and filter out, with computer assistance, how the detected patterns of defects correlate with the known types of tumors, response rates and other parameters. From these findings they can then take the next step of deriving prognoses and therapy approaches. In a multicenter study led by the Munich Leukemia Laboratory under Dr. Torsten Haferlach, correlations of no less than 95% have already been found between certain genetic defect patterns and courses of the disease.

The leukemia expert Dr. Bullinger: “All this research takes us a long ways towards developing new means of therapy with well-targeted effects. They could soon take away much of the horror of leukemia.”

Contact:

B&K Medien- und Kommunikationsberatung GmbH
Dr. Birgit Kofler; Daniela Pedross, MA.
Porzellangasse 35/Top 3, A-1090 Vienna
Phone: 0043-(0)676-6368930; Fax: 0043-01-319-43-78-20
E-Mail: kofler@bkkommunikation.at ; pedross@bkkommunikation.at

About EHA

The European Hematology Association (EHA) aims to promote excellence in clinical practice, research and education in European hematology.
Today, EHA – with over 2600 active members from 95 countries – is a consolidated organization that pursues a large and growing number of projects and programs. An Executive Board and Councilors elected by the membership form the governmental body responsible for the strategy and organization of the association.

About the EHA Annual Congress

The EHA annual congress is organized every June in a major European city. Over the years the congress has become the meeting place for hematologists in all fields of the speciality. The congress program has sessions on clinical and laboratory hematology and covers all the major hematological subspecialties, including hemato-oncology, red cell disorders, hemostasis, thrombosis, pediatric hematology and transfusion medicine.