Mutant Gene Linked to Aggressive Leukemia

Researchers have identified a common genetic change in Philadelphia chromosome ¹ (BCR-ABL1)-positive acute lymphoblastic leukemia (ALL), an aggressive leukemia that carries a poor prognosis. The change alters the gene IKZF1, which produces the protein Ikaros, and appears to be an important lesion in this ALL subtype, the researchers reported online in the April 13 Nature.

Ikaros plays a key role in regulating the normal development of lymphocytes ². The IKZF1 gene alterations were detected as part of an ongoing effort ³ to identify genetic abnormalities in ALL. Dr. James Downing of St. Jude Children's Research Hospital and his colleagues analyzed DNA copy number changes in 304 ALL cases, including 21 children and 22 adults with BCR-ABL1-positive disease.

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The IKZF1 gene was deleted in more than 80 percent of the BCR-ABL1 ALL cases. The deletions resulted in reduced expression of Ikaros or the expression of abnormal forms of the protein. "The discovery of this molecular lesion gives us important insights into the genetic pathways that are disrupted in BCR-ABL1 ALL," said Dr. Downing. "These results could ultimately lead to more effective treatments."

The researchers also analyzed 23 cases of chronic myelogenous leukemia (CML), which also involves BCR-ABL1 and is commonly treated with imatinib (Gleevec). Left untreated, CML may progress from an indolent stage to an acute leukemia known as blast crisis. The researchers observed Ikaros deletions at the progression of CML to lymphoid blast crisis, suggesting that Ikaros mutations help determine the behavior of BCR-ABL1 leukemia.

"BCR-ABL1 is the hallmark of CML, but this disease is complex," noted lead author Dr. Charles Mullighan of St. Jude. "Our results show that other genetic lesions are involved in the progression of CML to blast crisis, and in de novo BCR-ABL1 ALL. These additional lesions may be critical in the response of these diseases to treatment."

Chromosome Region Linked to Lung Cancer

A region of chromosome 15 may contain genetic risk factors for lung cancer, three research teams reported online this month in Nature and Nature Genetics. The results are from the first genome-wide association studies to attempt to identify the genetic component of a disease that is closely associated with a strong environmental cause. Yet researchers have long known that genetic factors play a role in lung cancer risk, and recent studies have implicated this region in the disease.

More work is needed to identify which DNA sequences in the region are responsible for the increased risk observed in the studies. The leading suspects are three genes that produce proteins on the cell surface that bind to nicotine, triggering a cascade of cellular changes, including some related to cancer. These proteins may contribute to cancer in the absence of exposure to nicotine.

The studies were led by Dr. Kari Stefansson of deCODE Genetics ⁴ in Iceland; Dr. Paul Brennan of the International Agency for Research on Cancer ⁵ in Lyon, France; and Dr. Christopher Amos of the University of Texas M.D. Anderson Cancer Center ⁶. The results provide strong evidence for a link between DNA variants on chromosome 15 and lung cancer, but the studies differ on whether the connection is direct or mediated through smoking behavior, according to an accompanying commentary in Nature ⁷.

Even larger studies with detailed information about smoking patterns and addictive behavior will be needed to discern whether "these discoveries relate to the risk of smoking, the risk of lung cancer, or the risk of both," write Drs. Stephen Chanock of NCI's Division of Cancer Epidemiology and Genetics and David Hunter of the Harvard School of Public Health.

IV Iron Effective in Treating Chemotherapy-Induced Anemia

Two studies in the April 1 Journal of Clinical Oncology (JCO) found that intravenous (IV) iron significantly improves hemoglobin levels in patients taking erythropoietin-stimulating agents (ESAs) for chemotherapy-induced anemia compared with ESAs alone or ESAs plus oral iron.

Anemia occurs in up to 75 percent of cancer patients who undergo chemotherapy or radiation treatment in clinical trials, and ESA therapy has been found to correct the blood condition in only 50 to 70 percent of patients.

In the first JCO study ⁸, 86 percent of patients receiving the ESA darbepoetin alpha (Aranesp) plus IV iron achieved either a hemoglobin level of at least 12 g/dL or an increase of at least 2 g/dL over their baseline hemoglobin level, compared with 73 percent of patients who received the ESA alone or ESAs with oral iron. Patients receiving IV iron responded more quickly to ESA therapy, achieving target hemoglobin levels in a median of 50 days compared with 64 days for patients not receiving IV iron.

In the second study ⁹, 76.7 percent of patients receiving darbepoetin alpha with IV iron achieved target hemoglobin levels, compared with 61.8 percent of patients receiving ESA therapy alone.

Last month, the U.S. Food and Drug Administration's Oncologic Drug Advisory Committee recommended substantially limiting the use of ESAs ¹⁰ to treat anemia in cancer patients after clinical trials showed an increased mortality risk in patients using ESAs to achieve hemoglobin levels of 12 g/dL or higher.

However, in an editorial accompanying the JCO articles, Dr. Michael Auerbach of Georgetown University writes: "These two studies add unique and useful information to a rapidly growing body of data supporting the routine use of IV iron as an adjunct to ESA therapy in appropriately selected oncology patients."