shankar jan
Badges: 9
Rep:
?
#1
Report Thread starter 2 years ago
#1
Is the fusion Bcr-Abl protein the same thing as Abl kinase?

I think this is what implies in the attachment.
Name:  Screenshot_20190827-221627_Xodo Docs.jpg
Views: 107
Size:  348.7 KB
0
reply
Svenjamin
Badges: 17
Rep:
?
#2
Report 2 years ago
#2
Yes, the Abl in Bcr-Abl fusion is Abl kinase, but they're not the same thing.

Abl kinase and Bcr are two genes that are found on completely different chromosomes - these genes are entirely 'normal' in function and are not oncogenes. In Philadelphia positive CML, recombination between Chr9 and Chr22 results in a mutated gene that is the Bcr and Abl genes fused together, hence Bcr-Abl fusion. This recombinant (hybrid) gene is an oncogene that drives the malignant cell growth, since kinases phosphorylate genes, which forces gene activation.

It's also worth noting that Gleevec is the brand name of the medication. The generic name is Imatinib. So Gleevec/Imatinib are often used interchangeably.
Last edited by Svenjamin; 2 years ago
1
reply
Jpw1097
Badges: 19
Rep:
?
#3
Report 2 years ago
#3
(Original post by Svenjamin)
Yes, the Abl in Bcr-Abl fusion is Abl kinase, but they're not the same thing.

Abl kinase and Bcr are two genes that are found on completely different chromosomes - these genes are entirely 'normal' in function and are not oncogenes. In Philadelphia positive CML, recombination between Chr9 and Chr22 results in a mutated gene that is the Bcr and Abl genes fused together, hence Bcr-Abl fusion. This recombinant (hybrid) gene is an oncogene that drives the malignant cell growth, since kinases phosphorylate genes, which forces gene activation.

It's also worth noting that Gleevec is the brand name of the medication. The generic name is Imatinib. So Gleevec/Imatinib are often used interchangeably.
This answer is spot on. Not much else I’d like to add.
0
reply
shankar jan
Badges: 9
Rep:
?
#4
Report Thread starter 2 years ago
#4
(Original post by Svenjamin)
Yes, the Abl in Bcr-Abl fusion is Abl kinase, but they're not the same thing.

Abl kinase and Bcr are two genes that are found on completely different chromosomes - these genes are entirely 'normal' in function and are not oncogenes. In Philadelphia positive CML, recombination between Chr9 and Chr22 results in a mutated gene that is the Bcr and Abl genes fused together, hence Bcr-Abl fusion. This recombinant (hybrid) gene is an oncogene that drives the malignant cell growth, since kinases phosphorylate genes, which forces gene activation.

It's also worth noting that Gleevec is the brand name of the medication. The generic name is Imatinib. So Gleevec/Imatinib are often used interchangeably.
Thanks so much for your reply!This cleared up so many doubts.
Just was wondering if you could please check this for me if possible?

Where you kindly mentioned "kinases phosphorylate genes, which forces gene activation" - However, I thought kinases phosphorylate proteins only and not genes. Kinases phosphorylate proteins which leads to protein activation - is this right?

"This recombinant (hybrid) gene is an oncogene that drives the malignant cell growth, since kinases phosphorylate genes, which forces gene activation."
Please could you let me know if this is correct?
The Bcr-Abl fusion protein is not a kinase because the activity of a kinase is regulated but this Bcr-Abl fusion is always activated.
The gene product from the Bcr gene on chromosome 22 is a kinase.
The gene product from the Abl gene on chromosome 9 is a kinase.
However, the gene product from the Bcr-Abl oncogene on the philadelphia chromosome is not a kinase, it is just called the Bcr-Abl fusion protein.

Regarding my 2nd attachment (I have also attached it here below): How can the Abl kinase inhibitor be a drug used in treatment of CML patients? I thought this drug would do bad than good - this is because the Abl kinase inhibitor is targeting the Abl kinase produced by a normal cell and not the Bcr-Abl fusion protein which is produced by an unhealthy (or even already cancerous) cell. So why the Abl kinase inhibitor?
Name:  40.PNG
Views: 107
Size:  314.4 KB
Last edited by shankar jan; 2 years ago
0
reply
shankar jan
Badges: 9
Rep:
?
#5
Report Thread starter 2 years ago
#5
(Original post by Svenjamin)
Yes, the Abl in Bcr-Abl fusion is Abl kinase, but they're not the same thing.

Abl kinase and Bcr are two genes that are found on completely different chromosomes - these genes are entirely 'normal' in function and are not oncogenes. In Philadelphia positive CML, recombination between Chr9 and Chr22 results in a mutated gene that is the Bcr and Abl genes fused together, hence Bcr-Abl fusion. This recombinant (hybrid) gene is an oncogene that drives the malignant cell growth, since kinases phosphorylate genes, which forces gene activation.

It's also worth noting that Gleevec is the brand name of the medication. The generic name is Imatinib. So Gleevec/Imatinib are often used interchangeably.
Sorry! Accidentally attached the wrong attachment in my reply back to you - I have just fixed it! Apologies for the inconvenience!!
0
reply
Svenjamin
Badges: 17
Rep:
?
#6
Report 2 years ago
#6
(Original post by shankar jan)
Thanks so much for your reply!This cleared up so many doubts.
Just was wondering if you could please check this for me if possible?

Where you kindly mentioned "kinases phosphorylate genes, which forces gene activation" - However, I thought kinases phosphorylate proteins only and not genes. Kinases phosphorylate proteins which leads to protein activation - is this right?

"This recombinant (hybrid) gene is an oncogene that drives the malignant cell growth, since kinases phosphorylate genes, which forces gene activation."
Please could you let me know if this is correct?
The Bcr-Abl fusion protein is not a kinase because the activity of a kinase is regulated but this Bcr-Abl fusion is always activated.
The gene product from the Bcr gene on chromosome 22 is a kinase.
The gene product from the Abl gene on chromosome 9 is a kinase.
However, the gene product from the Bcr-Abl oncogene on the philadelphia chromosome is not a kinase, it is just called the Bcr-Abl fusion protein.

Regarding my 2nd attachment (I have also attached it here below): How can the Abl kinase inhibitor be a drug used in treatment of CML patients? I thought this drug would do bad than good - this is because the Abl kinase inhibitor is targeting the Abl kinase produced by a normal cell and not the Bcr-Abl fusion protein which is produced by an unhealthy (or even already cancerous) cell. So why the Abl kinase inhibitor?
Attachment 845370
In response to your first question - you're right, kinases phosphorylate proteins, which then affect gene activation. Apologies, I was being clumsy.

In regards to kinase inhibitors, I'm no expert, but I believe this is why dosage is important. You want to influence the malignant cells but not the healthy cells. As malignant cells are wildly multiplying, they will be more susceptible to drugs that inhibit kinases since they're using these pathways far more than healthy cells. If the dose was increased massively, the drugs would have massive side effects on healthy cells. As it is, drugs that inhibit cell division still often have fairly severe side effects as there's no way to make them 100% specific to the cancer.

It's why development of kinase inhibitors involves selection for specificity. As with many drugs, a slight adjustment to the chemical structure will change the drug's specificity for the drug target. Basically, they started with a general inhibitor that inhibited cancer but also inhibited healthy cells (it works, but bad side effects!), but then tweaked it slightly and found that it was more specific for the cancer protein and less specific for the healthy protein. Over many iterations, they eventually have their drug which is highly specific for the Bcr-Abl fusion, with (hopefully) minimal side effects and also means they can minimise dosage for a therapeutic effect to further reduce drug toxicity.

This is also why the cancer becomes resistant. The specific kinase inhibitor inibits the proteins of susceptible cells with that specific drug target, but there may be that cells with mutations where the protein lacks the target (e.g. slight conformational changes to the protein change the target enough that the drug won't bind effectively). In this way, cancer resistance to drugs is similar to microbial resistance to antibiotics - once you kill off all the susceptible cells, you're left with just the resistant cells. If these continue to multiple, you need to find a different kinase inhibitor.

These are the basic concepts, but someone else might be able to provide more details or find clumsy errors in my explanation. This is outside of my ballpark! Brian Drucker developed Gleevec - I'm sure there's plenty of literature on the history of its development if you look for reviews discussing his work.

(One final thought that I'm not sure if it's true in this case so please don't take for gospel but would be logical: cells often have salvage pathways that can compensate if another pathway is blocked. The back up pathway may be not quite as effective, but it can do the job. There are hundreds of kinases and dozens of pathways. However, the cancer cell with its mutated Bcr-Abl *needs* that pathway to propagate accelerated growth. There may be other oncogenes present, but this mutation is a prime driver of malignance, which is why it's a unifying characteristic in 95% of CML cases. So this could be another reason why healthy cells aren't so badly effected. I'm not sure if this is the case for this specific example, but it's a general principle seen in other areas.)
Last edited by Svenjamin; 2 years ago
0
reply
Svenjamin
Badges: 17
Rep:
?
#7
Report 2 years ago
#7
(Original post by shankar jan)
Thanks so much for your reply!This cleared up so many doubts.
Just was wondering if you could please check this for me if possible?

Where you kindly mentioned "kinases phosphorylate genes, which forces gene activation" - However, I thought kinases phosphorylate proteins only and not genes. Kinases phosphorylate proteins which leads to protein activation - is this right?

"This recombinant (hybrid) gene is an oncogene that drives the malignant cell growth, since kinases phosphorylate genes, which forces gene activation."
Please could you let me know if this is correct?
The Bcr-Abl fusion protein is not a kinase because the activity of a kinase is regulated but this Bcr-Abl fusion is always activated.
The gene product from the Bcr gene on chromosome 22 is a kinase.
The gene product from the Abl gene on chromosome 9 is a kinase.
However, the gene product from the Bcr-Abl oncogene on the philadelphia chromosome is not a kinase, it is just called the Bcr-Abl fusion protein.

Regarding my 2nd attachment (I have also attached it here below): How can the Abl kinase inhibitor be a drug used in treatment of CML patients? I thought this drug would do bad than good - this is because the Abl kinase inhibitor is targeting the Abl kinase produced by a normal cell and not the Bcr-Abl fusion protein which is produced by an unhealthy (or even already cancerous) cell. So why the Abl kinase inhibitor?
Name:  40.PNG
Views: 107
Size:  314.4 KB
And to add, Bcr-Abl is still a kinase. Just because it's unregulated doesn't stop it being a kinase. The name "kinase" refers to its chemical activity (catalysing phosphorylation), not the regulation of that activity.
Last edited by Svenjamin; 2 years ago
0
reply
shankar jan
Badges: 9
Rep:
?
#8
Report Thread starter 2 years ago
#8
(Original post by Svenjamin)
In response to your first question - you're right, kinases phosphorylate proteins, which then affect gene activation. Apologies, I was being clumsy.

In regards to kinase inhibitors, I'm no expert, but I believe this is why dosage is important. You want to influence the malignant cells but not the healthy cells. As malignant cells are wildly multiplying, they will be more susceptible to drugs that inhibit kinases since they're using these pathways far more than healthy cells. If the dose was increased massively, the drugs would have massive side effects on healthy cells. As it is, drugs that inhibit cell division still often have fairly severe side effects as there's no way to make them 100% specific to the cancer.

It's why development of kinase inhibitors involves selection for specificity. As with many drugs, a slight adjustment to the chemical structure will change the drug's specificity for the drug target. Basically, they started with a general inhibitor that inhibited cancer but also inhibited healthy cells (it works, but bad side effects!), but then tweaked it slightly and found that it was more specific for the cancer protein and less specific for the healthy protein. Over many iterations, they eventually have their drug with (hopefully) minimal side effects and also means they can minimise dosage for a therapeutic effect to further reduce drug toxicity.

This is also why the cancer becomes resistant. The specific kinase inhibitor inibits the proteins of susceptible cells with that specific drug target, but there may be that cells with mutations where the protein lacks the target (e.g. slight conformational changes to the protein change the target enough that the drug won't bind effectively). In this way, cancer resistance to drugs is similar to microbial resistance to antibiotics - once you kill off all the susceptible cells, you're left with just the resistant cells. If these continue to multiple, you need to find a different kinase inhibitor.

These are the basic concepts, but someone else might be able to provide more details or find clumsy errors in my explanation. This is outside of my ballpark!
Ah thank you so so much! I love it when I get things haha
Also, got me thinking....Malignant cells are multiplying very rapidly due to oncogenes coding for growth factors. The G1 phase of the cell cycle for maligant cells is much faster due to all those excessive growth factors. Cells in mitosis are affected by any growth factors or inhibitors up to the restriction point of the G1 phase. So at the same time that excessive growth factors are making the process of the maligant cell going into the S phase faster, a kinase inhibitor would suddenly stop the malignant cell from progressing into the S phase and the maligant cell would therefore go into the G0 phase.

I am not sure if I am right but hopefully it is
0
reply
Svenjamin
Badges: 17
Rep:
?
#9
Report 2 years ago
#9
(Original post by shankar jan)
Ah thank you so so much! I love it when I get things haha
Also, got me thinking....Malignant cells are multiplying very rapidly due to oncogenes coding for growth factors. The G1 phase of the cell cycle for maligant cells is much faster due to all those excessive growth factors. Cells in mitosis are affected by any growth factors or inhibitors up to the restriction point of the G1 phase. So at the same time that excessive growth factors are making the process of the maligant cell going into the S phase faster, a kinase inhibitor would suddenly stop the malignant cell from progressing into the S phase and the maligant cell would therefore go into the G0 phase.

I am not sure if I am right but hopefully it is
A quick search brought up a video of the creator(/discoverer?) of Gleevec, explaining how Gleevec works: https://youtu.be/d6xU3bgBLIw
0
reply
shankar jan
Badges: 9
Rep:
?
#10
Report Thread starter 2 years ago
#10
(Original post by Svenjamin)
A quick search brought up a video of the creator(/discoverer?) of Gleevec, explaining how Gleevec works: https://youtu.be/d6xU3bgBLIw
Thanks so much for the link
0
reply
Jpw1097
Badges: 19
Rep:
?
#11
Report 2 years ago
#11
(Original post by shankar jan)
Thanks so much for your reply!This cleared up so many doubts.
Just was wondering if you could please check this for me if possible?

Where you kindly mentioned "kinases phosphorylate genes, which forces gene activation" - However, I thought kinases phosphorylate proteins only and not genes. Kinases phosphorylate proteins which leads to protein activation - is this right?

"This recombinant (hybrid) gene is an oncogene that drives the malignant cell growth, since kinases phosphorylate genes, which forces gene activation."
Please could you let me know if this is correct?
The Bcr-Abl fusion protein is not a kinase because the activity of a kinase is regulated but this Bcr-Abl fusion is always activated.
The gene product from the Bcr gene on chromosome 22 is a kinase.
The gene product from the Abl gene on chromosome 9 is a kinase.
However, the gene product from the Bcr-Abl oncogene on the philadelphia chromosome is not a kinase, it is just called the Bcr-Abl fusion protein.

Regarding my 2nd attachment (I have also attached it here below): How can the Abl kinase inhibitor be a drug used in treatment of CML patients? I thought this drug would do bad than good - this is because the Abl kinase inhibitor is targeting the Abl kinase produced by a normal cell and not the Bcr-Abl fusion protein which is produced by an unhealthy (or even already cancerous) cell. So why the Abl kinase inhibitor?
Name:  40.PNG
Views: 107
Size:  314.4 KB
BCR and ABL are separate genes on chromosomes 22 and 9 respectively. In CML, the BCR and ABL genes fuse forming the Philadelphia chromosome. Now, the fused BCR-ABL gene coded for a protein (just as every other gene does) - this protein is the Bcr-Abl fusion protein, now with unregulated kinase activity. The Bcr-Abl fusion protein is still a kinase. The Bcr-Abl protein will phosphorylate various proteins leading to activation of various signalling pathways that promote cellular proliferation.

Imatanib is a tyrosine kinase inhibitor that is pretty selective for the Bcr-Abl kinase, so it has minimal effects on healthy cells.
0
reply
shankar jan
Badges: 9
Rep:
?
#12
Report Thread starter 2 years ago
#12
(Original post by Jpw1097)
BCR and ABL are separate genes on chromosomes 22 and 9 respectively. In CML, the BCR and ABL genes fuse forming the Philadelphia chromosome. Now, the fused BCR-ABL gene coded for a protein (just as every other gene does) - this protein is the Bcr-Abl fusion protein, now with unregulated kinase activity. The Bcr-Abl fusion protein is still a kinase. The Bcr-Abl protein will phosphorylate various proteins leading to activation of various signalling pathways that promote cellular proliferation.

Imatanib is a tyrosine kinase inhibitor that is pretty selective for the Bcr-Abl kinase, so it has minimal effects on healthy cells.
Thank you very much!!!
0
reply
X

Quick Reply

Attached files
Write a reply...
Reply
new posts
Back
to top
Latest
My Feed

See more of what you like on
The Student Room

You can personalise what you see on TSR. Tell us a little about yourself to get started.

Personalise

Has your education been disrupted this academic year due to the pandemic?

Yes (6)
100%
No (0)
0%

Watched Threads

View All