London, April 15 : Experts at St. Jude Children's Research Hospital have unearthed evidence that a combination of genetic mutations is to blame for most cases of acute lymphoblastic leukemia (ALL), which often proves fatal.
Given that a series of genetic mutations work together cause the disease, the researchers have named these defects 'cooperating oncogenic lesions'.
The researchers have revealed that these defects include the deletion of a gene called IKZF1, whose protein Ikaros normally helps guide the development of a blood stem cell into a lymphocyte.
They have also discovered that the loss of the same gene accompanied the transformation of chronic myelogenous leukaemias (CMLs) to a life-threatening acute stage.
"These findings provide new avenues to pursue to gain a better understanding of these disease processes and, ultimately, to develop better therapies," Nature magazine quoted Dr. James R. Downing, St. Jude scientific director and chair of the Department of Pathology, as saying.
He says that his team's findings lend further support to the idea that malignancies frenquently require mutations in multiple genes in order to develop.
Dr. Downing says that cells contain oncogenes, which exist harmlessly until something triggers them to turn the cells malignant.
"It really takes a series of genetic lesions to lead to cancer. You may get activation of an oncogene, but you may also need activation of a tumor suppressor gene and an alteration in a cell-death pathway," he said.
In a previous study, the researchers tried to identify genetic differences between CML and a form of acute leukaemia known as BCR-ABL1 ALL.
Both diseases are characterized by the Philadelphia chromosome, which results from the translocation (joining) of parts of two different chromosomes, and the result of this translocation is the expression of BCR-ABL1, an oncogene.
"It appears from our study, and other work published previously, that all you need to get CML is that chromosomal translocation and BCR-ABL1 expression," Dr. Downing said.
In their latest study, the researchers re-examined the genetic makeup of 304 ALL patients who had been studied earlier, including 43 paediatric and adult BCR-ABL1 ALL patients and 23 adults with CML.
The number of genetic mutations found in the original gene survey was increased using a more sensitive technology.
In the first study, the gene most commonly altered was one called PAX5, followed by a gene designated IKZF1, whose protein Ikaros is involved in the development and differentiation of B lymphocyte cells, which are part of the immune system.
"The vast majority of pediatric acute lymphoblastic leukemias are of B-cell lineage," Downing said.
The researchers said that among the ALL patients, they found an average of 8.79 copy number alterations, a form of genetic change linked to the development and progression of cancer. The most common change was deletion of the gene for Ikaros, they added.
The gene was deleted in 83.7 per cent of the BCR-ABL1 ALL patients, including 76.2 per cent of the paediatric and 90.9 per cent of the adult cases.
"The loss of the Ikaros gene is a nearly obligatory lesion for the development of BCR-ABL1 ALL, and clearly must be a genetic lesion that is cooperating with BCR-ABL1," Dr. Downing said.
In their study report, the researchers wrote that a gene known as CDKN2A was deleted in 53.5 per cent of the BCR-ABL1 ALL patients, 87.5 per cent of whom also had lost the gene for Ikaros.
The PAX5 deletion occurred in 51 per cent of the BCR-ABL1 ALL patients, and 95 per cent of such people were missing the Ikaros gene.
Among the CML patients, whose disease converted to ALL, two out of three had the deletion of the Ikaros gene. A lower percentage of those who converted to acute myeloblastic leukemia had the same gene deleted.
The researchers said that those findings suggested that the deletion of Ikaros was cooperating with BCR-ABL1 to cause ALL.
"That is an important finding that may give insight into how that transformation occurs, or it may give insight into a better way to treat the disease, if one can figure out how the Ikaros deletion is working," Dr. Downing said.