Ask A Scientist Molecular Biology Archive

name         Mark
status       other
age          40s
  
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?
----------------------------------------

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
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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. 

NEWTON AAS
Div. of Educational Programs
Argonne National Laboratory
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