Leukemia is one of the most common forms of cancer. This dreadeddisease of the blood occurs when one of the stem cells that gives riseto mature white blood cells mutates. This mutated cell growsuncontrollably, crowding out other blood cells and interfering withtheir normal functioning.
Although leukemias are relatively easy to bring under control byinjecting chemotherapy drugs into the bloodstream, the side effectsof these toxic drugs are unpleasant, at best, and dangerous, at worst.To complicate matters even further, chemotherapy is rarely able toeliminate the last abnormal cell. As a result, the disease usuallyreturns, often in a form that is resistant to the drugs already used.
While they affect adults and children of all ages, leukemias come intwo basic types. One is a chronic disease in which progression isslow, allowing patients to live for many years after initial diagnosis.The other is acute disease in which progression is rapid and patientsdie quickly. In acute leukemias, an important marker of the disease isthe fusion of a variety of other genes to the ALL1 gene located onchromosome 11. This fusion and other genetic rearrangements seenin leukemias are usually visible as chromosomal translocations.
A new genetic mechanism, potentially explaining the developmentof some acute leukemias, is presented in an article in the Feb. 15issue of the Journal of the American Medical Association. In thispaper, Steven Schichman and his colleagues at the Thomas JeffersonUniversity Medical School in Philadelphia and Weizmann Institutein Israel present their findings that the ALL1 gene can also fuse toitself in acute leukemias. They report on the importance of this generearrangement for the progression of the disease and how this newfinding should help clinicians who are diagnosing acute leukemias.
Structure Of The ALL1 Gene Self-Fusion
Although the normal functions of the ALL1 gene and its role in theonset of leukemia are still unclear, much is known about this gene'sstructure. As described in the Schichman article, the ALL1 proteinshares three regions of similarity with the trithorax protein ofDrosophila melanogaster. The trithorax gene regulates the expressionof genes responsible for the development of the body and wings ofthe fruit fly.
In addition, the amino terminal region of the ALL1 protein bears astrong similarity to a portion of the methyltransferase protein thatrecognizes methylated DNA, the latter being characteristic of genesequences whose expression is shut off. The authors conclude thatthese structural features indicate that the ALL1 gene may help toregulate the development and differentiation of blood stem cells.
As Schichman and colleagues report, when the ALL1 gene fuses toother genes, the fused genes contain the amino terminus of the ALL1protein and the carboxy terminus of the other genes. Mostimportantly, when self-fusion occurs, it also preserves the aminoterminus of the ALL1 gene. As the authors state, the amino terminaldomains that include the methyltransferase remain, suggesting thatthey are critical for leukemia development.
The surprise that awaited these scientists was that self-fusion of theALL1 gene could also happen and that it occurred without the usualvisible chromosomal translocations.
In a news release, Schichman, an oncologist, commented on thesignificance of the discovery of the self-fusion gene.
"We were interested specifically whether there could be anyrearrangement of the ALL1 gene in patients for whom no visiblechromosomal rearrangements were present," Schichman said. "Iworked with this for several months . . . The gene was rearrangedand I was trying to find the structure of the rearrangement. When Ifinally solved the problems, I realized that I had discoveredsomething wonderful, something unexpected, and something thatwas bound to help people in the future."
Molecular Diagnosis Of Leukemia
While chromosomal translocations indicate that the ALL1 geneparticipates in 5 percent to 10 percent of acute leukemias, the newfinding of self-fusion means that this number must be at leastdoubled. Because these leukemias do not have visible chromosometranslocations, rearrangement of the ALL1 gene by self-fusion canonly be detected by molecular techniques. Currently, reversetranscriptase-polymerase chain reaction is used to detect fusion genetranscripts and amplify them to a measurable level. As Schichmanpoints out, rapid diagnostics can be made in a clinical setting from adrop of blood or bone marrow.
The molecular detection of self-fusion is particularly important in thedesign of a successful therapeutic regimen for harder to treatleukemias. As Schichman told BioWorld Today, the discovery ofALL1 gene self-fusion will provide a means of identifying asubgroup of patients with poor prognosis and high risk of relapse.The paper's authors point out that by recognizing this patientsubgroup early on, they may benefit from aggressive management,including bone marrow transplantation, at an early stage of thedisease.
The ALL1 self-fusion gene defect is acquired at some point duringcell growth, resulting in a loss of normal growth control. As a result,Schichman said researchers believe that acquiring the genetic defectis "the initiating event in the formation of these leukemias."
He added, "The identification of gene defects in leukemia is veryimportant because the defects lay the foundation for all future studiesregarding how the leukemia grows and behaves. They also lay thefoundation for the development of future therapies for thoseleukemias. Whenever you identify a gene defect, you have apotential target for therapy in the future. Prior to identifying theALL1 self-fusion defect, we didn't know how these leukemiasoccurred on a genetic basis, and now we do." n
-- Chester Bisbee Special To BioWorld Today
(c) 1997 American Health Consultants. All rights reserved.