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Cover-worthy cells attack cancer via a novel mechanism

It wasn't quite the equivalent of appearing on the cover of Time as Person of the Year, but DMS researcher Ruth Craig, Ph.D., was pretty pleased to get her cells on the cover of the journal Blood—and not just once, but twice. Well, they weren't exactly her cells, but cells she's lived with for a long time. Cells so important that when she moved to Dartmouth from Johns Hopkins, they were transported from Logan Airport to Hanover by chauffeured van.

Cells: After earning a master's in pharmacology at Boston University and her doctorate at SUNY Buffalo, Craig did a postdoctoral stint at Harvard's Dana Farber Cancer Institute and then joined the faculty at Johns Hopkins. She and her cells moved to Dartmouth in 1993. By that time, she had already discovered in her particular white blood cell line a new gene, MCL1 (myeloid cell leukemia-1), and the protein that this gene encodes. A patent on that protein was issued in March of 1999.

Ruth Craig, and a blow-up of one of her covers for the journal Blood.
Photograph by Joseph Mehling (email)

Craig, an associate professor of pharmacology and toxicology at DMS, has focused for many years on the molecular mechanisms involved in the induction of cell differentiation—the process by which some cells mature and acquire characteristics or functions different from those of the original cells.

For this work, it was natural to select a differentiating hematopoietic cell line. She was looking for a gene or genes that controlled differentiation in her cells, with the idea that such a discovery might lead eventually to ways of preventing the conversion of normal cells into cancer cells or of inducing cancer cells to differentiate back into normal cells. Upon the induction of differentiation, her cells remain viable but lose the capacity to divide. When she programmed for differentiation, she noted both increases and decreases in the expression of a number of genes. Among the genes showing an increase in expression was a novel one, MCL1.

Gene: Many genes involved in cancer fall into families based on similarities in their nucleotide sequences, but at the time of Craig's discovery only one other gene seemed to be related to hers—the BCL2 (B cell lymphoma- 2) gene. BCL2, which is involved in the development of lymphomas, inhibits apoptosis, or the programmed cell death that occurs as part of the normal cellular life cycle. If cell death is prevented by MCL1 or BCL2, the cell may go on to develop into a cancer cell. Thus, MCL1 and BCL2 are antiapoptotic genes.

Since then, a host of other genes in the BCL2 family have been discovered. Other oncogenes, or cancer-causing genes, either promote cell growth directly or suppress some factor that normally inhibits cell growth. The BCL2 family, however, seems to cause cancer by a novel mechanism involving the prevention of cell death. The probability of developing cancer increases as one grows older. The longer one lives, the greater the chance is that some cellular event may go awry and result in a cancer. Similarly, the longer cells live in a culture, the greater the chance is that some other influence will transform them into cancer cells. At that point, with BCL2, other genes must promote cell growth because growth, along with invasion and metastasis, are the hallmarks of cancer.

Craig's first cover for Blood compares photomicrographs of control cells and cells induced to express MCL1 genes after both had been treated with a toxic anticancer drug. The control cells were dying by apoptosis, but the cells induced to express MCL1 remained viable. The second cover was an extension of the work represented in the first and showed that if one uses specific cells from MCL1 transgenic mice and places them in the correct environment, MCL1 can participate in immortalization— a necessary prelude to cancer.

But why would one want to patent a gene or protein that seems to cause cancer? There are several possible beneficial applications. One lies in the fact that increased expression of the protein product could be measured in tissues or blood and thus serve as an early diagnostic test for some forms of cancer. Another possible application is that manipulation of the MCL1 protein might be a fruitful avenue to explore as a possible way to treat or prevent cancer. Like a number of proteins, MCL1 undergoes phosphorylation —part of the metabolic process. Indeed, it is likely that it undergoes multiple phosphorylation reactions, some of which could lead to activation of the protein and others to its inactivation.

Action: The novel action of these genes, coupled with the observation that they are expressed in a variety of cells and in a tissue-specific manner, suggests their applicability to many cancers. The next step will be to test these hypotheses in animals in which cancer has been induced. Results so far in mice have been very encouraging, which should facilitate Craig's hope of someday conducting human trials.

Along the way, she has made a second discovery related to the genomic sequence of MCL1, which suggests other commercial applications. This finding also was deemed worthy of a patent, but until the patent has actually been issued she is keeping its exact nature under wraps.

Roger P. Smith, Ph.D.

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