Leukemias come in two life-expectancy versions, chronic and acute.Chronic leukemia connotes a lengthy survival; acute leukemia (ALL),in adults, often a relatively swift death sentence even with moderntherapy.In the U.S., some 35 people per million population _ young and adult_ develop acute leukemia every year.Most leukemias are thought to arise when chromosomes misbehave.Sometimes, for reasons unknown, a chromosome will duplicate someof its DNA, to produce trisomy _ a triple dose, instead of a double.Such trisomies are a common hallmark of leukemia. Chromosomesalso tend to swap stretches of their DNA packages, a phenomenoncalled translocation. This is also frequently leukemogenic.The translocation connection was first established in 1960 at theUniversity of Pennsylvania in Philadelphia, by a tumor cytogeneticistnamed Peter Nowell. He reported that patients with chronicmyelogenous leukemia invariably carried a chromosome 22 with apiece missing from its long arm. For reasons of geography, this hassince been known as "the Philadelphia chromosome." Its missingfragment later turned up on chromosome 9, which had translocated bitsof its arm with 22.Researchers have found that a gene for acute leukemia (ALL-1) onchromosome 11 translocates with other genes on other chromosomes,and that 5 to 10 percent of acute human leukemias display thesereciprocally fused genes. A paper in the current Proceedings of theNational Academy of Sciences (PNAS) reports that "Partial duplicationof ALL-1, in which a portion of a putative protooncogene is fused withitself, represents an additional mechanism for leukemogenesis," andthat trisomy in malignant cells may indicate such protooncogeneduplication.Peter Nowell, discoverer of the Philadelphia chromosome, toldBioWorld Today, "This (paper) is the first example in which we havesomething to explain the circumstance that we've seen at a muchcruder level for many years: Where there's an extra dose of achromosome, we've never been able previously to determine whatspecific gene is involved." He added, "This indicates for the first timethat we're not talking about a single extra dose of a gene, but aparticular type of gene rearrangement."The paper's lead author, hematopathologist Steven Schichman, is aresearch instructor at the Cancer Institute of Thomas JeffersonUniversity, also in Philadelphia. He explained the crucialrearrangement to BioWorld Today:"What we found by molecular studies was that the ALL-1 gene isrearranged by duplication of a portion encoding the amino terminus ofits protein. Although this protein has been cloned, we haven't a clue asto its function."ALL-1 Gene Translocates With 30 Partner GenesThe ALL-1 gene, Schichman continued, "is unique, because itreciprocally translocates with as many as 30 different partner genes, allinvolved in acute leukemia. Four or five of these have been cloned sofar; they don't seem to share any common structural features.""This suggested," he added, "that the partner genes themselves werenot contributing a common primary function for development ofleukemia, and that the important contribution came from the tandemduplication of the portion of ALL-1 that encodes the protein's aminoterminus."He found the gene in peripheral blood or bone marrow from acuteleukemia patients. "Its frequency in such patients," he said, "waspreviously thought to be between 5 and 10 percent of human acuteleukemia. These estimates were based on looking at translocatedchromosomes through the microscope."His molecular probes suggest that the chromosome 11 self-rearrangement "is as common as all the other ALL-1 genetranslocations combined _ in fact, may account for up to one-half. Buteven this represents only a very population of patients in absolutenumbers _ a few hundred a year in the U.S.""We are now in the process of screening several hundred patients, todetermine with accuracy the frequency of this rearrangements in adultswith acute leukemia," Schichman said.Turning to trisomies in general, he observed, "People have ascribed theconstant association of various chromosomal trisomies in leukemia to a`dosage effect,' that is, getting an extra dose of something, but didn'tknow of what."He stated that three out of four cases he and his principal investigator,Carlo Croce studied, "had this particular rearrangement of the ALL-1gene in a trisomic chromosome 11 without any other suspectedleukemia genes."Nowell observed of the PNAS paper: "Any time you have a structuralalteration in a gene, you have a potential specific target for diagnosisand therapy." But he continued, "The big problem with this, involvinga very small handful of patients, is not just developing the therapy, butwho's going to spend the money to do it."Nowell noted that even before new therapies come on the scene,finding the ALL-1 gene "in pediatric acute leukemias, which carry abad prognosis, may be important in making decisions about therapiesalready available, such as bone marrow transplantation." n

-- David N. Leff Science Editor

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