Vol 3. Issue 39 / December 20, 2004

A Molecular Cause for Leukemia

By Jason Socrates Bardi

In many walks of life, the word "fusion" is filled with the hope of promising new combinations. Fusion cuisine delivers never before sampled flavors, such as pumpkin sage spring rolls. Jazz fusion evokes mid-century musicians turning a corner and forging ahead—think late Miles Davis. Fusion energy fuels the sun and, its advocates claim, may someday deliver cheap energy on earth if technology can harness it.

On the other hand, not all these combinations work as intended. Jazz fusion led to smooth jazz. Pumpkin sage spring rolls taste awful. Cold fusion didn't work at all.

In nature, fusion can be something more sinister. The abnormal fusion of two chromosomes—an event that cancer biologists refer to as translocation—is one of the hallmarks of cancer. Many patients who suffer from acute myeloid leukemia, for instance, have translocation events and fusion proteins at the heart of their condition.

Acute myeloid leukemia is caused when hematopoietic blood cell precursors acquire mutations in their DNA that corrupt their normal gene expression and signal transduction machinery. One such mutation causes an abnormal protein called AML1-ETO to arise. About 12 percent of patients with acute myeloid leukemia have this translocation.

AML1-ETO is a molecular Frankenstein's monster formed by the fusion of the two separate chromosomes, 8 and 21, which encode the proteins "AML1" (also called RUNX1) and "ETO" (also called MTG8). The AML1 gene is at one end of chromosome 8, and the ETO gene is at an end of chromosome 21.  When the two chromosomes fuse, these two genes are dragged together forming a new, longer gene coding for AML1-ETO. AML1 is a DNA binding transcription factor. AML1-ETO contains AML1 DNA binding domain. AML1-ETO protein then causes deregulation of transcription leading to a swarm of gene expression and the corruption of the normal process of differentiation whereby the hematopoietic cells turn into specialized red and white blood cells. Instead, these cancerous blood cells divide and divide in a precursor stage of differentiation.

Associate Professor Dong-Er Zhang, who is a member of the Department of Molecular and Experimental Medicine at The Scripps Research Institute, has made several models of the fusion protein in acute myeloid leukemia.

One of the conclusions that she and other scientists have reached in the last few years is that other mutations are contributing to acute myeloid leukemia that have not yet been identified. "AML-ETO is required but not enough for leukemia development," says Zhang.

So where are these other mutations associated with translocation and the development of leukemia? Some of them, says Zhang, may be in a domain at the C-terminal end of the AML1-ETO protein.

Shorter Protein Strongly Induces Leukemia

In an upcoming issue of the journalProceedings of the National Academy of Sciences, Zhang and her colleagues at Scripps Research are reporting that they have shown that one end of the AML1-ETO protein, the C-terminal end, is particularly important for acute myeloid leukemia—when it's not there.

In mouse studies, they observed that a single nucleotide change in this C-terminal domain leads to a truncated form of AML1-ETO. This truncated protein strongly induces leukemia.

"If you delete this domain, you really induce leukemia," says Zhang.

The detailed mechanism of how this works is still unclear, but it has to do with the way in which the AML1-ETO C-terminus interacts with other proteins. Several groups of scientists in the last few years have published reports showing that this C-terminal domain interacts with proteins called NCoR and SMRT that are corepressors for gene expression.

Protein transcription is important for leukemia and malignant neoplasms—the name for the cancer cells that are present in the bloodstream of patients with leukemia. In order to multiply, these neoplasms need to make duplicate copies of themselves. Full-length AML1-ETO including its C-terminal NCoR/SMRT interacting domain actually arrests the growth of the cancer cells.

But if the AML1-ETO protein is truncated and its C-terminus cannot bind to the co-repressors, then the transcription is not repressed, and the neoplasm is free to copy its DNA and continue to divide.

"Now we have narrowed down a particular area to look for new mutations in AML1-ETO and its down stream signaling pathways and study leukemia development," says Zhang.

The article, "Deletion of an AML1-ETO C-terminal NcoR/SMRT Interacting Region Strongly Induces Leukemia Development" is authored by Ming Yan, Sebastien A. Burel, Luke F. Peterson, Eiki Kanbe, Hiromi Iwasaki, Anita Boyapati, Robert Hines, Koichi Akashi, and Dong-Er Zhang is available online at: http://www.pnas.org/cgi/content/short/101/49/17186. The article also appears in the December 7, 2004 issue of the journal Proceedings of the National Academy of Sciences.

This work was supported by the National Institutes of Health and The Skaggs Institute for Research.


Send comments to: jasonb@scripps.edu











"Now we have narrowed down a particular area to look for new mutations in AML1-ETO and its down stream signaling pathways [to] study leukemia development."

-Dong-Er Zhang