St. Jude Children’s Research Hospital scientists 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 journalBlood.
The work focused on Philadelphia chromosome-positive ALL (Ph-positive ALL), a high-risk cancer that accounts for about 40 percent of ALL in adults and about 5 percent in children. The disease is named for a chromosomal rearrangement that brings together pieces of the BCR and ABL genes. That leads to production of the BCR-ABL protein, which fuels the unchecked cell growth that is a hallmark of cancer.
In this study, researchers identified the protein MCL1 as the partner in crime of BCR-ABL. MCL1 is one of several proteins that can block the process of programmed cell death known as apoptosis. The body uses apoptosis to eliminate damaged, dangerous or unneeded cells. The research demonstrates that MCL1 is essential for preventing apoptosis of leukemia cells.
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, Ph.D., an associate member of the St. Jude Department of Biochemistry. “That is exciting because we already have drugs like imatinib 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.”
Tyrosine kinase inhibitors are designed to block the BCR-ABL protein. The drugs have revolutionized treatment of chronic myeloid leukemia (CML), which strikes adults and includes the same chromosomal rearrangement as Ph-positive ALL. But results of TKI treatment were less dramatic for adults and children with Ph-positive ALL, and drug resistance remains a problem.
For this study, researchers combined one of two tyrosine kinase inhibitors, imatinib or dasatnib, 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. MCL1, BCL-2 and BCL-XL work to prevent cell death, even cancer cell death, by blocking the activity of proteins that promote the process.
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,” Opferman said.
Earlier discoveries made by the Opferman laboratory revealed that MCL-1 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 Opferman’s laboratory.
Factors that may increase your risk of developing some types of leukemia include:
Previous cancer treatment. People who’ve had certain types of chemotherapy and radiation therapy for other cancers have an increased risk of developing certain types of leukemia.
Genetic disorders. Genetic abnormalities seem to play a role in the development of leukemia. Certain genetic disorders, such as Down syndrome, are associated with increased risk of leukemia.
Certain blood disorders. People who have been diagnosed with certain blood disorders, such as myelodysplastic syndromes, may have an increased risk of leukemia.
Exposure to high levels of radiation. People exposed to very high levels of radiation, such as survivors of a nuclear reactor accident, have an increased risk of developing leukemia.
Exposure to certain chemicals. Exposure to certain chemicals, such as benzene - which is found in gasoline and is used by the chemical industry - also is linked to increased risk of some kinds of leukemia.
Smoking. Smoking cigarettes increases the risk of acute myelogenous leukemia.
Family history of leukemia. If members of your family have been diagnosed with leukemia, your risk of the disease may be increased.
However, most people with known risk factors don’t get leukemia. And many people with leukemia have none of these risk factors.
In this study, the investigators showed that MCL1 was required for cancer cell survival throughout the Ph-positive ALL disease process, beginning when white blood cells known as B lymphocytes were transformed from normal to tumor cells.
Scientists showed that deleting Mcl1 from the leukemia cells of mice blocked cancer’s progression and turned the mice into long-term survivors.
The other authors are Jeffrey Morrison, Rhonda Perciavalle, Harpreet Singh and Richard Williams, all formerly of St. Jude; and Jerold Rehg of St. Jude.
Your child is considered low-risk if:
she is between age 1 and 10
she has less than 50,000 white blood cells per cubic millimetre (mm3) of blood when she is diagnosed
Children with low-risk ALL must also have the following biological features:
leukemia cells with chromosome changes that respond well to treatment. These cells either have a translocation of chromosome 12 and 21 or three copies of chromosomes 4, 10 and 17.
no leukemic cells in the cerebrospinal fluid (CSF), which means your child has a negative CNS status.
a good response to the first phase of chemotherapy (induction). As mentioned above, doctors determine this by looking at your child’s MRD status at the end of induction therapy. When children respond well to initial treatment, it is called having a rapid early response (RER) treatment.
Your child is considered high risk if she has either one of the following features:
less than age one or older than ten years of age
more than 50,000 white blood cells/mm3 of blood when she is diagnosed
a large amount of leukemic cells in the spinal fluid, which means your child has a positive CNS status
leukemia cells with chromosome changes that are more difficult to treat. In these cells, a part of one chromosome breaks, and fuses to a gene on another chromosome involved in leukemia, called MLL. This is called an MLL gene rearrangement.
For example, a child with ALL who is 12 years old but has a white blood cell count less than 50,000/mm3 at diagnosis will be considered high risk.
Very high-risk ALL
Children with very high-risk ALL may also have certain chromosome changes inside their leukemia cells. These include:
leukemia cells that have parts of chromosome 9 and chromosome 22 fused together. This is called a Philadelphia chromosome.
leukemia cells which have too few chromosomes (hypodiploid)
The study was supported in part by a grant (HL102175) from the National Institutes of Health, the American Cancer Society and ALSAC.
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