Protein That Promotes Survival Of Stem Cells Might Be Key To Poor Leukemia Prognosis

Mcl-1 blocks the biochemical cascade of reactions that trigger apoptosis ("cell suicide") of HSCs, according to Joseph Opferman, Ph.D., assistant member of St. Jude Biochemistry. Expression of Mcl-1 thus ensures that HSCs continue to thrive and multiply so they can complete the task of making huge numbers of blood cells. This process is extremely important during the initial development of the blood system before birth. Expression of Mc1-1 is also crucial for maintaining blood cells throughout life as red and white cells and platelets die and must be replaced. HSCs are also needed to rebuild the blood system of patients undergoing chemotherapy and radiation for cancer. Opferman completed work on this project while a member of Stanley Korsmeyer's laboratory at the Dana-Farber Cancer Institute (Boston).

Mcl-1 belongs to the Bcl-2 family of proteins. Some of these family members promote apoptosis, while others prevent it. "Other researchers have previously shown that members of the Bcl-2 family that block apoptosis are involved in regulating the number of HSCs and progenitor cells," Opferman said. "But our study showed for the first time that a single such Bcl-2 family protein--Mcl-1--is essential for promoting the survival of these cells."

Progenitor cells are precursors arising from HSCs; these cells produce daughter cells that become increasingly specialized and then produce specific types of blood cells, such as B lymphocytes--immune cells that produce antibodies.

"Understanding the role of Mcl-1 in apoptosis and how this gene is regulated will help my lab at St. Jude understand why some cases of leukemia are so difficult to cure," Opferman said. "The more we understand these diseases, the more likely we'll be able to design improved treatments for them. This fits into the St. Jude mission of finding cures for catastrophic diseases of childhood, such as leukemia, in order to save lives."

The importance of Mcl-1 lies in the differing roles it plays in health and disease.

"On one hand, this protein keeps HSCs and progenitor cells alive and multiplying so the body can maintain its needed supply of blood cells," he said. "However, Mcl-1 also prevents the abnormal white blood cells found in leukemia from undergoing apoptosis in response to chemotherapy or radiation. This makes the leukemia cells resistant to treatments designed to damage the cell so it undergoes apoptosis." Opferman is continuing his studies of Mcl-1 at St. Jude to better understand the role this protein plays in both normal hematopoiesis (production of blood cells) as well as in potentially fatal blood cancers.

Opferman and his colleagues had previously shown that Mcl-1 is needed to ensure that HSCs and progenitor cells produced by HSCs are able to generate more specific cells, such as the immune cells known as B and T lymphocytes.

In the Science study, Opferman's team genetically modified mice so that the gene for Mcl-1 could be specifically deleted from the genome of HSCs and progenitor cells. Upon genetic deletion, these mice developed anemia and had severely reduced numbers of bone marrow (BM) cells, such as HSCs and progenitor cells. This was strong evidence that Mcl-1 was needed to maintain these cell populations.

The team also demonstrated that BM cells lacking Mcl-1 did not multiply when removed from mice and cultured in the laboratory. However, BM cells with the gene continued to flourish. In contrast, liver cells were unaffected following loss of Mcl-1, demonstrating that Mcl-1 is important only in certain cell types. Finally, the investigators showed that growth factors (natural proteins that stimulate cells to grow), such as the "stem cell factor," trigger the expression of the Mcl-1 gene. This was an important clue to how cells control the powerful effects of Mcl-1.

Other authors of this study are Hiromi Iwasaki, Christy C. Ong, Heikyung Suh, Shin-ichi Mizuno, Koichi Akashi and Stanley J. Korsmeyer (Dana-Farber Cancer Institute).

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This study was supported in part by the Damon Runyon Cancer Research Foundation, the Leukemia and Lymphoma Society, the Howard Hughes Medical Institute and the National Institutes of Health.

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