St. Jude's Study Yields New Strategy Against High-Risk Leukemia
St. Jude Children’s Research Hospital investigators have identified a protein that certain high-risk acute lymphoblastic leukemia (ALL) cells need to survive and have used that knowledge to fashion a more effective method of killing tumor cells. The findings appear in the August 29 edition of the journal Blood.
The work focused on Philadelphia chromosome–positive ALL, a high-risk cancer that accounts for about 40% of ALL in adults and about 5% in children. In this study, researchers identified the protein MCL1 as essential for preventing apoptosis of leukemia cells.
Novel Drug Pairing
Investigators combined drugs that reduce MCL1 levels in leukemia cells with a second drug that targets another protein that inhibits cell death. The pairing increased apoptosis in human leukemia cells growing in the laboratory.
“These findings suggest that disrupting the ability of leukemia cells to produce MCL1 renders those cells vulnerable to other drugs,” said corresponding author Joseph Opferman, PhD, an Associate Member of the St. Jude Department of Biochemistry. “That is exciting because we already have drugs like imatinib [Gleevec] and other tyrosine kinase inhibitors that reduce MCL1 production in tumor cells, leaving those cells vulnerable to being pushed into death via apoptosis by other drugs already in development.”
The researchers combined one of two tyrosine kinase inhibitors, imatinib or dasatnib (Sprycel), with the experimental drug navitoclax. The latter drug disrupts the ability of the proteins BCL-2 and BCL-XL to protect cancer cells from apoptosis. Along with MCL1, BCL-2 and BCL-XL are members of a family of proteins that regulate apoptosis.
Since MCL1 is elevated in a number of cancers and is associated with cancer-drug resistance, a similar two-drug approach might also enhance the effectiveness of tyrosine kinase inhibitors for treatment of other cancers. “We are very interested in pursuing this strategy,” Dr. Opferman said.
Other Findings
Earlier discoveries made by the Opferman laboratory revealed that MCL1 also protects heart health by preventing loss of heart muscle cells through apoptosis. “Together these findings suggest that MCL1 is a relevant target for cancer treatment, but efforts should focus on diminishing the expression of MCL1, rather than completely eliminating its function,” said first author Brian Koss, a staff scientist in Dr. Opferman’s laboratory.
In this study, the investigators showed that MCL1 was required for cancer cell survival throughout the Philadelphia chromosome–positive ALL disease process, beginning when B lymphocytes were transformed from normal to tumor cells.
The study was supported in part by a grant (HL102175) from the National Institutes of Health, the American Cancer Society, and ALSAC.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
