Hi Ruth - from my understanding it is your variant allele frequency (VAF) which is the approximate % of your cells at this point in time that have the JAK2 mutation. Mine is 15% when I checked last year. I asked to have this test (my MPN specialist did not include it in my original tests), as his view is that there isn’t clear evidence this metric is correlated with your actual thrombotic/event risk. I think if it increases to a much higher point, it could indicate that or indicate you could be moving to PV, but there would be other markers in your blood test for that. Some of the treatments will lower your VAF overall. Others on this site have a better understanding and lived experience with this, so will let them comment!

Dear Ruth,

Ren explained well what VAF% means.
The thing with our mutations is that there will be changes over time in how many of the cells will be affected and sometimes treatment helps reduce the allele burden in some people. This research is largely performed in people with JAK2V617F mutation.

It is not straightforward how allele burden influence the illness, as one can have not only driver mutations (i.e., JAK2, MPL, CALR), but also additional somatic mutations (e.g., "ASXL1, SRSF2, and IDH2 in PV, and SH2B3/LNK, SF3B1, U2AF1, TP53, IDH2, and EZH2 in ET") that can complicate the picture. From what I could read, it is difficult to make a prognosis based on only VAF %, there are efforts to integrate VAF in risk calculation, but this is still an early effort:
https://www.mdpi.com/2073-4409/10/8/1962

https://www.nature.com/articles/s41588-023-01638-x

https://www.sciencedirect.com/science/article/a...

In the studies above you can read that both very low and very high VAF regarding JAK2V617F mutation holds some risk, showing that there isn't a linear relationship between the allele burden and illness burden. Also, in some people who have inherited MPNs, the allele burden is going to be >50%, and there the risk is down to the type of mutation rather than the allele burden.

There is a simplistic effort to say more than 50% means more chances for transformation or the need to reconsider classifying ET/PV as myelofibrosis, but myelofibrosis can be diagnosed only based on bone marrow biopsy, and many people with high VAF do not have any signs of myelofibrosis. Another suggestion is that VAF >50% means inherited illness, and this holds true for younger patients. My VAF is 53%, my dad had ET that transformed into myelofibrosis, his mom had undiagnosed ET.

We are in the infancy of discovering how VAF is influencing our illness. My personal hope is to never acquire additional somatic mutations, as those are not good news in terms of prognosis. But even there there research is just starting to understand how that happens.

Best wishes,
Tatiana

Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms - Nature Genetics

https://www.nature.com/articles/s41588-023-01638-x

Integration of Molecular Information in Risk Assessment of Patients with Myeloproliferative Neoplasms

https://www.mdpi.com/2073-4409/10/8/1962

Thank you Tatiana and Ren.!

You have helped me a great deal. And the references and comments that you provide All the time Tatiana had Convinced me Earlier that you are very well educated in a scientific field.

I am DVM With PhD s in Pathology and toxicology. My Fascinating Career in big Pharm Was cut Short By cognitive decline Which Overlaps With four years of Increased 100,000 above normal not Being Picked up PCP . He has apologized profusely.

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I do Have a keen Interest In all of the references you Selected. Excellent journals.

Thanks for your extra effort . You have much to be proud of!

With appreciation and Best wishes to both you and Ren!!

Ruth

Dear Ruth,

Ren explained well what VAF% means.
The thing with our mutations is that there will be changes over time in how many of the cells will be affected and sometimes treatment helps reduce the allele burden in some people. This research is largely performed in people with JAK2V617F mutation.

It is not straightforward how allele burden influence the illness, as one can have not only driver mutations (i.e., JAK2, MPL, CALR), but also additional somatic mutations (e.g., "ASXL1, SRSF2, and IDH2 in PV, and SH2B3/LNK, SF3B1, U2AF1, TP53, IDH2, and EZH2 in ET") that can complicate the picture. From what I could read, it is difficult to make a prognosis based on only VAF %, there are efforts to integrate VAF in risk calculation, but this is still an early effort:
https://www.mdpi.com/2073-4409/10/8/1962

https://www.nature.com/articles/s41588-023-01638-x

https://www.sciencedirect.com/science/article/a...

In the studies above you can read that both very low and very high VAF regarding JAK2V617F mutation holds some risk, showing that there isn't a linear relationship between the allele burden and illness burden. Also, in some people who have inherited MPNs, the allele burden is going to be >50%, and there the risk is down to the type of mutation rather than the allele burden.

There is a simplistic effort to say more than 50% means more chances for transformation or the need to reconsider classifying ET/PV as myelofibrosis, but myelofibrosis can be diagnosed only based on bone marrow biopsy, and many people with high VAF do not have any signs of myelofibrosis. Another suggestion is that VAF >50% means inherited illness, and this holds true for younger patients. My VAF is 53%, my dad had ET that transformed into myelofibrosis, his mom had undiagnosed ET.

We are in the infancy of discovering how VAF is influencing our illness. My personal hope is to never acquire additional somatic mutations, as those are not good news in terms of prognosis. But even there there research is just starting to understand how that happens.

Best wishes,
Tatiana

Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms - Nature Genetics

https://www.nature.com/articles/s41588-023-01638-x

Integration of Molecular Information in Risk Assessment of Patients with Myeloproliferative Neoplasms

https://www.mdpi.com/2073-4409/10/8/1962

I don’t know but at least your Hematologist told you what your levels are.

Mine did not. So much I don’t know I’m supposed to know.
Just that I have JAK2.

Someone on here will be able to help you.