(This article originally appeared in the January 1996 issue of the Cener for Cancer Research Newsletter and has been edited and reprinted with permission.)
Many cancers are associated with a genetic malfunction in which part of one chromosome has broken off and joined with another chromosome. When such chromosomal translocations occur, genes from one chromosome can come under aberrant control by genetic elements on the other.
A group of MIT biologists and colleagues has recently characterized a translocation that causes a form of leukemia. Specifically, they have identified the genes that are disrupted by the translocation. They did this by first identifying the sites where the chromosomes broke.
The work, reported in this month's Nature Genetics, will allow development of rapid tests for monitoring the progression, therapy, remission and relapse of acute myeloid leukemia. It should also provide valuable insights into the development of leukemia.
The MIT team is led by Professor David E. Housman of the Center for Cancer Research (CCR) and the Department of Biology. Other MIT scientists involved in the work are Julian Borrow and Amanda M. Shearman, both of whom have postdoctoral appointments at the CCR, and Vincent P. Stanton, a CCR visiting scientist. The work was done with collaborators from laboratories and hospitals around the world.
WHAT IS LEUKEMIA?
Leukemias are cancers of blood cells and there are many different types. Acute myeloid leukemia (AML) is a cancer of a subset of white cells normally responsible for combating bacterial infections. These cells are called myeloid cells and each of us makes many, many millions of such cells each day. The remarkable thing is that virtually all of those cells are born, do their jobs appropriately, and die each day of our lives for many decades; we make as many as we need to fight infections and no more.
Leukemia develops when such cells or their precursors multiply too much or fail to die. The resulting excess numbers of cells accumulate in the blood and tissues, leading to the clinical problems associated with leukemia. A basic question, therefore, is what goes wrong to cause this excessive production of myeloid cells in AML?
Like many other cancers, AML is frequently associated with specific chromosomal translocations. When this happens, parts of one gene can become fused with parts of a second gene to produce a fusion gene, which encodes a fusion protein made of parts of two independent proteins. Such fusion proteins can interfere with the regulation and behavior of cells.
The Housman lab and colleagues focused on a translocation between chromosomes 7 and 11 that is frequently associated with AML. Cells and DNA from AML patients showing this translocation served as the raw material for the hunt for the gene or genes at the translocation breakpoints on chromosomes 7 and 11.
Using a series of elegant molecular genetic methods, which the Housman lab has played a major role in developing in recent years, they progressively homed in on the genes responsible. The search initially used fusion of patients' cells with hamster cells to isolate the translocated, derivative chromosomes and molecular genetic markers to map more precisely which parts of the two chromosomes become fused. Then they made a detailed map of the relevant part of human chromosome 7 and located the breakpoint by comparison with the derivative chromosomes. Active genes in this region were then identified.
The first exciting result came there: the breakpoint fell in a set of genes known as the HOXA cluster. HOX genes are responsible for regulating many fundamental aspects of development. Originally described in flies (and incidentally, one of the discoveries recognized by the 1995 Nobel prize in medicine or physiology) they encode master regulatory genes that encode proteins which bind to DNA and control the expression of other sets of genes. Humans have four major clusters of HOX genes, and the HOXA cluster on chromosome 7 has previously been implicated in the control of blood cell development. So it was an exciting result to discover that the breakpoint associated with AML fell in the HOXA cluster, specifically in the HOXA9 gene.
With that gene in hand, the Housman lab used it to identify and isolate the other (chromosome 11) side of the junction from the derivative chromosome. Here came the second exciting discovery: the relevant gene on chromosome 11 encodes a protein of the nuclear pore complex, called NUP98. Nuclear pore complexes are made up of many proteins including NUP98 and several related proteins. These appear to act as gatekeepers to the nucleus, binding and transporting material (e.g., proteins, RNA) moving into and out of the cell's nucleus. Thus, nuclear pores and NUP98 sit at another important site in the cell controlling many crucial cellular functions.
The discovery of the fusion of the NUP98 and HOXA9 genes in this translocation thus leads to the fusion of three exciting and very active areas of biological research: genetic regulation of cellular development by HOX genes, control of nuclear import and export, and the mechanisms of oncogenic transformation in myeloid leukemia.
Like many breakthroughs, this one raises as many interesting questions as it answers.
Clearly, further work on the HOXA cluster and the nuclear pore complex and their potential roles in controlling proliferation, differentiation and survival of myeloid cells should provide valuable insights into the development of leukemia.
Collaborators on the work include researchers from the West German Cancer Center, Brigham and Women's Hospital, the University of Toronto, Great Ormond Street Hospital in London, Queen Mary Hospital in Hong Kong, Christchurch School of Medicine in New Zealand, Tokyo Medical College and the University of Chicago Medical Center. The work was supported by the NIH, SERC (UK), and the Leukemia Society of America.