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Name: Mark
Status: Other
Age: 40s
Location: N/A
Country: N/A
Date: September 2002


Question:
Is the Philadelphia Gene (which causes CML Leukemia) inherited?

My Mother-In-Law has this type of Leukemia and she is afraid she has passed this gene on to her daughter (my wife).

But according to Dr. Selina Luger of the Abramson Cancer Center of the University Of Pennsylvania it can not be passed on to your children. But according NEWTON (from this forum) there is a 50% chance it can be passed on to your children.

Who is right?



Replies:
Yes, it can be. This is a very complicated subject. The Philadelphia chromosome (named because it was discovered at hospital in Philadelphia), is actually what is known as a balanced, or reciprocal, translocation. What this means is that early in cell division a process known as crossing over occurs. This is when the tip of each of a a pair of chromosomes breaks off and switches places. This increases genetic variety in a species and is one of the reasons that no two organisms are exactly alike (unless they are clones). Sometimes the pieces don't switch places correctly. One of the errors that can happen is called a translocation. A piece of one of the chromosome pairs doesn't make it to the other to trade and actually attaches to another chromosome that isn't its pair. In the "Philadelphia chromosome" a piece of chromosome 9 attaches to chromosome 22.

It is a reciprocal translocation because part of 22 also attaches to 9. Other types of translocations occur when the piece attaches to the other chromosome but they don't trade info. The information that piece carries is inserted next to another gene and causes what is known as a "fusion protein." This means that the two parts now work together to form a new message. The gene from chromosome 9 is called "abl" and the gene from 22 is called "bcr." "Abl" is a gene that plays a role in normal cell division. Because the exchange is reciprocal, two different forms are made. If the genes are in the bcr-abl order, this causes the CML, because bcr makes abl stay turned on longer than normal and causes prolonged cell division. If the genes are in the abl-bcr, or the mirror image on the other chromosome product, this doesn't happen.

A new drug marketed as Gleevec, is able to turn off the abl gene causing the cancer cells to stop dividing. So to answer your question: yes, you can inherit the Philadelphia chromosome if you inherit the one that has the genes in the bcr-abl order. But this only increases the chances that you may get this cancer. You could also inherit the other form, which would not increase your chances of cancer. There is a whole cascade of events that must happen to cause CML, so inheriting the Philadelphia chromosome doesn't mean instant cancer, but it does mean that you already have one strike against you when you are born. You and your siblings could all inherit this form and none of you may get cancer, some may get it, or all of you may get it. I have checked the available literature on line and although I did not find anything that said specifically that these types of translocations can be inherited, it was implied many times. I would talk to the doctor again, and armed with this information, ask for a more thorough explanation. She probably has more specific information.

vanhoeck


Dear Mark:

As you may know, the Philadelphia chromosome "results from reciprocal translocation...[of]...the 9q chromosome [that] contains the proto-oncogene abl....to chromosome #22, where it fuses with BCR. This BCR-abl fusion product has a tyrosine kinase activity which the c-abl lacks" ( http://www.byz.org/~sev/Personal/school/mcb135g/mech.html ), and it "stimulates unrestrained division of white blood cells" ( http://www.sonoma.edu/users/c/cannon/115Chapter11.html ). Thus, it is "often found in the white blood cells of patients with chronic myeloid leukemia" ( http://helios.bto.ed.ac.uk/bto/glossary/p.htm ), and "bone marrow cells that contain the Philadelphia chromosome are often found in chronic myelogenous leukemia", as well ( http://www.upci.upmc.edu/internet/glossary/glossar2p.htm ).

However, it seems that this translocation is not inherited directly, since "the translocation between chromosomes 9 and 22 (the Philadelphia chromosome) in chronic myelogenous leukemia takes place exclusively between the paternally derived chromosome 9 and the maternally derived chromosome 22" ( http://bioneer.kaist.ac.kr/labs/molgenet/lectures/BM701/Imprinting/imp1. html ). Although the cause of this translocation has not yet been conclusively established, it might be possible for one's offsping to inherit a predisposition for such a translocation, but this would be the extent of any sort of heritable tendency. As far as I know, even this sort of genetic mechanism has not yet been observed.

Thus, it seems that CML results from a "somatic cell" translocation, "between the paternally derived chromosome 9 and the maternally derived chromosome 22" in a white blood cell precursor within the bone marrow causing its unrestricted proliferation, as opposed to a genetic defect that could be passed on through the "germ line cells".

So it would appear that Dr. Luger is correct, & you can reassure your mother-in-law that she cannot have directly passed the Philadelphia chromosome on to her daughter. As far as I can tell, there is no evidence that a predisposition for the translocation can be inherited, either.

As a coincidental aside, Dr. Luger is actually my mother's oncologist, as well, so it is reassuring to confirm that she is, in fact, an expert in her field.

Thanks very much for the interesting question. This fact was news to me, as well,

Jeff Buzby, Ph.D.
Children's Hosp. of Orange Cnty.



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