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Perplexing X in non-Hodgkin's lymphoma
By Haleh V. Samiei

Non-Hodgkin's lymphoma (NHL) refers to the many different cancers of white blood cells originating in the lymph nodes. The first step in the development of many NHLs involves chromosomal translocations—exchanges of pieces of DNA between unrelated chromosomes. This rearrangement often leads to aberrant production of RNA or protein from neighboring genes that may be important in maintaining the balance between cell growth and cell death.

Another chromosomal abnormality observed in many NHLs is the loss or gain of extra copies of the X chromosome. Carolyn Brown, of the Department of Medical Genetics at the University of British Columbia in Vancouver, Canada, and her colleagues at the British Columbia Cancer Agency are interested in the possible involvement of X chromosome genes in the development of NHL.

One of the two X chromosomes is inactivated in healthy females, so that they produce the same amounts of RNA and proteins from their genes as males who only have a single X chromosome. "Because X is an oddball, having the possibility of being inactive," says Brown, "I think a lot of people don't necessarily worry about it too much for its involvement in cancer."

Brown and colleagues set out to determine whether the extra X chromosome in females with NHL was active or inactive. They thought that, if the extra X were inactive, it would suggest problems with replication of chromosomes in NHL and not necessarily the involvement of X chromosome genes. If the X were active, however, it would suggest that X chromosome genes may actually play a role, says Brown. This is because many genes would produce twice as much RNA and proteins. Their findings are published in the July issue of Genes, Chromosomes & Cancer.

The results were not so simple. Brown's team found extra copies of both the inactive and the active X chromosome in females with NHL. The interesting thing about it though was that, although they were dealing with data from only a handful of patients, the extra copies of the active X were always associated with one type of translocation between chromosomes 14 and 18. "It is quite confusing to tease out which came first," says Brown, "whether gain of the X is because of it being a certain subtype or whether gain of an X is making it that subtype." She cautions, however, that they still need to verify the results for a larger number of patients.

During the course of the above investigation, the researchers also stumbled across a perplexing finding. Brown and colleagues noticed that, unlike the active X chromosome in healthy males and females, a region of the active X chromosome was shut down and inactive in NHL patients. This suggests that it may actually be the inactivity and not the over-activity of certain genes that plays a role in NHL.

Not much is known about the genes in this inactive region of the X chromosome except for the androgen receptor gene, which is involved in prostate cancer. Brown and colleagues, however, believe that another gene may be involved in NHL. "The good news is that with the sequencing of the human genome, very shortly we will know at least what all the genes are in that region," says Brown. "The hard question is to prove that the one that you think may be involved is actually involved."

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McDonald, H.L., Gascoyne, R.D., Horsman, D. & Brown, C.J. Involvement of the X chromosome in non-Hodgkin lymphoma. Genes Chromosomes Cancer 28, 246-257 (July 2000).

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