RFC Study p53 Deletion

[Guest guest]

Dave,

This is a very interesting point of discussion.

p53 is a protein responsible for causing cells to commit suicide when

something goes wrong. It is the means ultimately responsible for how

most chemotherapy works. What happens is that you inhibit an enzyme

and stress the cell, which then in an attempt to avoid making mistakes,

kills itself.

The gene located for the p53 protein is located on Chromosome 17p.

This is the p arm (long) arm of chromosome 17. The assumption is that

it is more difficult to induce cells missing p53 to die. With one gene

for p53 missing (deletion of 17p) and the other one likely mutated, the

cells are less able to die.

There are two points worth making here. First, there are many other

genes located on 17p and it is unclear whether the poor prognosis is

related to 17p or one of these other genes. The data indicate a

relationship between prognosis and 17p deletions specifically. Second,

there are other means for developing dysfunction of the p53 pathway.

Anyone on of the proteins involved might go awry. Thus, we see

abnormalities of p53 without 17p deletions.

Rick Furman, MD

>

> I wonder if someone can shed some light on this for me. I was under

the

> impression that the 17 and 53 deletions were virtually the same. I

was

> also under the impression that Fludarabine based treatments don't

work

> with these deletions. But according to this study, those with the 17

> deletion were included and had good results. Am I confusing something

> here? Thanks

> Dave

>

[Guest guest]

I believe there's a typo within Dr. Furman's reply in that the " p " of

17p refers to the short ( " petite " ) arm of chromosome 17.

The excerpt below is from " Genetic abnormalities in CLL " at Dr.

Hamblin's site and may be of interest, the link is: " http://mutated-

unmuated.blogspot.com/2008/03/genetic-abnormalities-in-cll.html " .

You may also find the following links informing, which ties in tp53

located at 17p13.1 to CD44 and that, in turn, within band 13 of the

petite arm of chromosome 11: " http://www.signaling-

gateway.org/update/updates/200809/nrc2470.html " , " http://www.ncbi.nlm.

nih.gov/sites/entrez?Db=gene & Cmd=ShowDetailView & TermToSearch=960 " ,

and " http://www.ncbi.nlm.nih.gov/sites/entrez?

Db=gene & Cmd=ShowDetailView & TermToSearch=7157 " .

As a tidbit of interest, " the protein and its corresponding gene were

named p53, in reference to the mass of the protein (53 kilodaltons) " .

Getting back to the initial inquiry it is noted that " the normal

function of p53 is important for the response to chemotherapy " It is

my understanding that this is why alemtuzumab is considered

relatively effective for those refractory to fludarabine, which I

believe (id est, the fludarabine) utilizes the p53 & in so doing

takes it out. Well here's the excerpt from within Dr. Hamblin's web

site.

" Genetic lesions associated with deletions of the short arm of

chromosome 17 (del17p13), which encodes the TP53 tumour-suppressor

gene, and the long arm of chromosome 11 (del11q23), which encodes the

ataxia telangiectasia mutated (ATM) gene, result in a loss of

function of TP53. TP53 is a transcription factor activated by strand

breaks in DNA. It can trigger apoptosis or cell-cycle arrest. Thus,

by controlling repair or elimination of cells with damaged DNA, TP53

maintains the integrity of the genome and prevents clonal

progression. ATM is a kinase that regulates TP53. Many cytotoxic

drugs require the ATM/TP53 pathway to be intact for them to be

effective. A simple screening test that assesses how intact this

pathway is has been described.[69] Defects in the ATM/TP53 pathway

constitute the strongest independent predictors for disease that is

resistant to standard treatment.

Deletions of the ATM gene do not produce such a severe syndrome as do

deletions of TP53, with some patients having a fairly benign disease

course. Possibly, for ATM function to be impaired, mutations are

necessary on the other ATM allele.[70] Conversely, Kalla and co

workers have identified other genes affecting regulation of the cell

cycle and apoptosis—namely NPAT, CUL5, and PPP2R1B—in the commonly

deleted 11q22-q23 segment, which might underlie the severity of the

chronic lymphocytic leukaemia.[71] "

[Guest guest]

Dr. Furman, I feel like we should be paying you tuition. : ) Most

interesting and informative. Thank you.

When time allows: How reliable are the tests to determine p53 function

or deletion?

Also, how reliable is p53 status at predicting response to chemotherapy

as a percentage - could there be other pathways that trigger apoptosis

in some cases?

~ Karl

[Guest guest]

Yes, you are correct. The p is the short arm of the chromosome.

Glad you picked it up.

>

> I believe there's a typo within Dr. Furman's reply in that the " p "

of

> 17p refers to the short ( " petite " ) arm of chromosome 17.

>

> The excerpt below is from " Genetic abnormalities in CLL " at Dr.

> Hamblin's site and may be of interest, the link is: " http://mutated-

> unmuated.blogspot.com/2008/03/genetic-abnormalities-in-cll.html " .

>

> You may also find the following links informing, which ties in tp53

> located at 17p13.1 to CD44 and that, in turn, within band 13 of the

> petite arm of chromosome 11: " http://www.signaling-

>

gateway.org/update/updates/200809/nrc2470.html " , " http://www.ncbi.nlm.

> nih.gov/sites/entrez?Db=gene & Cmd=ShowDetailView & TermToSearch=960 " ,

> and " http://www.ncbi.nlm.nih.gov/sites/entrez?

> Db=gene & Cmd=ShowDetailView & TermToSearch=7157 " .

>

> As a tidbit of interest, " the protein and its corresponding gene

were

> named p53, in reference to the mass of the protein (53

kilodaltons) " .

> Getting back to the initial inquiry it is noted that " the normal

> function of p53 is important for the response to chemotherapy " It

is

> my understanding that this is why alemtuzumab is considered

> relatively effective for those refractory to fludarabine, which I

> believe (id est, the fludarabine) utilizes the p53 & in so doing

> takes it out. Well here's the excerpt from within Dr. Hamblin's web

> site.

>

> " Genetic lesions associated with deletions of the short arm of

> chromosome 17 (del17p13), which encodes the TP53 tumour-suppressor

> gene, and the long arm of chromosome 11 (del11q23), which encodes

the

> ataxia telangiectasia mutated (ATM) gene, result in a loss of

> function of TP53. TP53 is a transcription factor activated by

strand

> breaks in DNA. It can trigger apoptosis or cell-cycle arrest. Thus,

> by controlling repair or elimination of cells with damaged DNA,

TP53

> maintains the integrity of the genome and prevents clonal

> progression. ATM is a kinase that regulates TP53. Many cytotoxic

> drugs require the ATM/TP53 pathway to be intact for them to be

> effective. A simple screening test that assesses how intact this

> pathway is has been described.[69] Defects in the ATM/TP53 pathway

> constitute the strongest independent predictors for disease that is

> resistant to standard treatment.

>

> Deletions of the ATM gene do not produce such a severe syndrome as

do

> deletions of TP53, with some patients having a fairly benign

disease

> course. Possibly, for ATM function to be impaired, mutations are

> necessary on the other ATM allele.[70] Conversely, Kalla and co

> workers have identified other genes affecting regulation of the

cell

> cycle and apoptosis—namely NPAT, CUL5, and PPP2R1B—in the commonly

> deleted 11q22-q23 segment, which might underlie the severity of the

> chronic lymphocytic leukaemia.[71] "

>