Scientists at St. Jude Children?s Research Hospital in Memphis, Tennessee (USA), have identified a protein that certain high-risk acute lymphoblastic leukemia (ALL) cells need to survive and have used that knowledge to develop a two-drug combination therapy that offers a more effective method of killing tumor cells. In doing so, they have give new hope to children and adults with the disease. The findings appear in the August 29, 2013 online edition of the journal Blood.

The scientists focused on Philadelphia chromosome-positive ALL (Ph-positive ALL), a high-risk cancer that accounts for about 40% ofALL in adults and about 5% in children. The disease is named for a chromosomal rearrangement that brings together pieces of the BCR and ABL genes. This leads to production of the BCR-ABL protein, which fuels the unchecked cell growth that is a hallmark of cancer.

…. Disrupting the ability of leukemia cells to produce MCL1 renders those cells vulnerable to other drugs…

ALL is an aggressive type of leukemia characterized by the presence of too many lymphoblasts or lymphocytes in the bone marrow and peripheral blood. It can spread to the lymph nodes, spleen, liver, central nervous system (CNS), and other organs. Without treatment, ALL usually progresses quickly.

MCL1 and apoptosis
In this study,supported in part by the National Institutes of Health, the American Cancer Society and ALSAC,researchers identified the protein MCL1 as the partner- in-crime of BCR-ABL. MCL1, a Bcl-2 family protein antagonist, is one of several proteins involved in the regulation of apoptosisor programmed cell death (the protein canblock the process)versus cell survival, and in the maintenance of viability but not of proliferation. The protein mediates its effects by interactions with a number of other regulators of apoptosis.

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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,? noted 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 (TKI) 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.

Two-drug combination
Researchers combined one of two tyrosine kinase inhibitors, imatinib (Gleevec? Novartis Pharmaceuticals Corporation) or dasatnib (Sprycel?,Bristol-Myers Squibb Company), with the experimental drug ABT-263 or navitoclax (Abbott/Abbvie)*. 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 explained.

A relevant target
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.

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.

For more information:
Koss B, Morrison J, Perciavalle RM, Singh H, Rehg JE, Williams RT, Opferman JT. Requirement for anti-apoptotic MCL-1 in the survival of BCR-ABL B-lineage acute lymphoblastic leukemia. Blood. 2013 Jul 23. [Epub ahead of print][Article][PubMed]

* In 2012 AbbVie discontinued the development of ABT-263, which was in Phase II development for the treatment of hematologic malignancies

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