St. Jude discovery offers new avenues to understanding an aggressive form of leukemia

04-14-2008

Finding that a combination of genetic mutations can cause an aggressive form of acute lymphoblastic leukemia could lead to new cancer-fighting therapies

Researchers at St. Jude Children¡¦s Research Hospital have discovered evidence that a series of genetic mutations work together to initiate most cases of an aggressive and often-fatal form of acute lymphoblastic leukemia (ALL).

These defects, known as "cooperating oncogenic lesions," include the deletion of a gene, IKZF1, whose protein, Ikaros, normally helps guide the development of a blood stem cell into a lymphocyte. The researchers also found that loss of the same gene accompanied the transformation of chronic myelogenous leukemias (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," said James R. Downing, M.D., St. Jude scientific director and chair of the Department of Pathology.

The new study, which he and his colleagues reported in the advance online publication of the journal "Nature," adds further support to a key concept in cancer genetics: Malignancies frequently require mutations in multiple genes in order to develop.

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," Downing said. "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."

St. Jude researchers sought to identify genetic differences between CML and a form of acute leukemia known as BCR-ABL1ƒ{positive ALL.

Both diseases are characterized by the Philadelphia chromosome, which results from the translocation (joining) of parts of two different chromosomes. 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," Downing said.

In their new study, the researchers re-examined the genetic makeup of 304 ALL patients who had been studied earlier. The group included 43 pediatric and adult BCR-ABL1 ALL patients and 23 adults with CML. Using a more sensitive technology, the scientists increased the number of genetic mutations found in their original gene survey.

In the first study, the gene most commonly altered was one called PAX5, followed by a gene designated IKZF1. Its 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.

Among the ALL patients, the researchers 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.

The gene was deleted in 36 (83.7 percent) of the BCR-ABL1 ALL patients, including 76.2 percent of the pediatric and 90.9 percent of the adult cases.

"The loss of the Ikaros gene is a nearly obligatory lesion for the development of BCR-ABL1 ALL," Downing said, "and clearly must be a genetic lesion that is cooperating with BCR-ABL1."

Moreover, a gene known as CDKN2A was deleted in 53.5 percent of the BCR-ABL1 ALL patients, 87.5 percent of whom also had lost the gene for Ikaros. The PAX5 deletion occurred in 51 percent of the BCR-ABL1 ALL patients; and 95 percent of these 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. That finding suggested that the deletion of Ikaros is 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," Downing said.

This work was supported by ALSAC. Mullighan was supported by grants from the National Health and Medical Research Council, the Royal Australasian College of Physicians and the Haematology Society of Australasia.

St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit www.stjude.org.