BioWorld International Correspondent

LONDON - Mutations in an estrogen receptor may trigger some types of leukemia in humans, a study with knockout mice suggests. The Swedish researchers who carried out the study, which demonstrated that estrogen receptor beta (ERb) plays a key role in regulating the development of blood cells, anticipate that drugs that activate ERb may be potent anticancer agents.

Jan- ke Gustafsson, professor of medical nutrition and biosciences at the Karolinska Institute in Stockholm, Sweden, told BioWorld International, "We are very excited by this discovery. We are hoping that ERb agonists may be active against cancer of tissues such as the prostate and the colon, as well as of the hematopoietic system. But this discovery is also important as a first step toward understanding the regulation of the immune system by estrogen."

Such an understanding may explain many of the differences in autoimmune diseases between men and women, as well as why some autoimmune diseases improve in women during pregnancy or when they are taking hormone replacement therapy, Gustafsson added. "Eventually we hope to have a much better picture of the numerous estrogen-associated immune system diseases," he said, "and once we have different agonists and antagonists for ERa and ERb, perhaps we can start to improve the treatment of these very debilitating diseases."

An account of the team's study appears in the May 5, 2003, issue of the Proceedings of the National Academy of Sciences in a paper by Gil-Jin Shim and colleagues, titled "Disruption of the estrogen receptor b gene in mice causes myeloproliferative disease resembling chronic myeloid leukemia with lymphoid blast crisis."

Gustafsson and his colleagues were the first to describe the second estrogen receptor, which they named ERb in 1995. Since then, they have been busy working out what its function is, as well as its interaction with ERa.

Their latest paper in PNAS reports observations of mice lacking both copies of the gene for ERb. "There is normally a lot of ERb on bone marrow cells, and we found that, if you remove it, you get an explosion of cell replication among hematopoietic stem cells," Gustafsson said.

As a result, there are more differentiated mature cells in the blood, such as megakaryocytes and granulocytes. Overall, in blood smears taken from the mice, the number of white blood cells was four times higher than normal, and the red blood cell count was reduced.

Gustafsson said, "This is typical of chronic myeloid leukemia in humans. Most interestingly, at about 1.5 years of age, you can also see immature cells in these mice, as well as excess numbers of mature cells invading tissues such as the spleen, liver and lung." In the liver, he added, it is possible to see pale, jelly-like masses of white blood cells with the naked eye.

What thrills Gustafsson most is that the gene for ERb is located on human chromosome 14, next to genes that, when mutated, are thought to be involved in causing leukemia. "Whether this is just a coincidence, or whether ERb mutations could be an initial hit in the development of leukemia, we don't know - but we are looking into this."

All the observations, he said, fit research findings showing that ERb has anti-proliferative effects. He and his team also found that, in mice lacking both genes for ERb, the prostate gland was enlarged and hyperplastic. Further studies also showed that the gene encoding the anti-apoptotic protein Bcl-2 was up-regulated in the prostates of the animals.

"So it appears that ERb is anti-proliferative in the prostate, just as it is in the hematopoietic system," Gustafsson said. "If you remove ERb, you get anti-apoptotic genes overexpressed, like Bcl-2, and you see increased replication of cells."

He pointed to additional evidence that the same may be true in the colon. The Women's Health Initiative, a study of hormone replacement therapy, part of which was halted last year because of an increase in invasive breast cancers in patients receiving combined therapy, also showed a 30 percent decrease in colon cancer.

"We are quite certain that ERb is involved there, too, because the only estrogen receptor in the colonic epithelium is ERb."

The finding could have implications for drug discovery programs aimed at discovering new anti-depressants. ERb, Gustafsson said, also seems to be the only estrogen receptor present in the raphe nucleus of the brain, a region with many serotonin-containing neurons. "As we know that estrogens can up-regulate serotonin content in the raphe nucleus, the hope is that ERb agonists could form alternatives to existing selective serotonin reuptake inhibitors," he said.

Currently, Gustafsson and his team are studying the phenotype of knockout mice lacking the entire estrogen biosynthesis machinery. "These animals are completely devoid of estrogen. We hope this will help us to obtain an even more detailed picture of the interaction between estrogens and the immune system," he said. The group also is planning to treat animal models of human leukemia, which nevertheless retain both types of estrogen receptor, to see if they can develop candidate drugs to treat hematological malignancies.