EARLY DETECTION OF JAK2 GENE COULD AVERT MPN DX

[socrates_8]

Hey guys...

Thought some of you might find the following copy of a POST I've just placed on MATES in Oz an interesting read...

Best wishes

Steve

(Sydney)

EARLY DETECTION OF JAK2 GENE COULD AVERT MPN DX

Post by MPN-MATE Admin » Sat Feb 15, 2025 1:42 pm

Afternoon all...

After having a read & cross-referencing a few articles, I decided that this POST has some extremely interesting findings...

From the time I first became diagnosed (Dx), I knew that there were some rather interesting symptoms I'd experienced, however, nobody connected them to the potential possibility of a rare type of blood cancer.

As most of you will already be aware of, it really wasn't until the discovery of the first "Driver–mutations" (Jak2, MPL & CALR) were uncovered that any real progress had been made in coming to understand the complexity behind what having an MPN might really look like etc.

Well here's a new and interesting fact, it may well prove to be, that people with either JAK2 or CALR, might have had that gene since being a young child or even to the point of near conception(?) And that many of the other mutations are somatically gained & compounded over the ensuing next 10-40 years.

These (Two) articles are suggesting that any disruptive intervention, (at early JAK2 / CALR discovery), may indeed alter the course & severity of any potential MPN condition.

I've provided the full reference information below, and the full-text can be read from using the DOI number included in those references etc.

Fascinating reading!

Best wishes

Steve

"MPN diagnosis is currently defined phenotypically, by blood count parameters and bone marrow histomorphology43. Our results indicate that the point at which a clinical diagnosis is made, represents one time-point on a continuous trajectory of lifelong clonal outgrowth, at which blood counts have reached certain thresholds, or clinical complications have already occurred. Current diagnostic criteria do not best capture when patients begin to have disease as life-threatening thromboses often trigger diagnosis. Furthermore, diagnostic criteria do not capture when individuals begin to be risk as those harbouring JAK2V617F in the general population have increased risk of thrombosis, altered blood count parameters and gravely increased risk of future MPN44. Our data show that mutant clones will generally have been present for 10 to 40 years before diagnosis and would have been detectable for much of this time using sensitive assays. Clonal fractions of 1%, the common cut-off used for population screening studies, already reflect decades of clonal outgrowth, and the rate of expansion of JAK2V617F strongly influences latency to disease presentation, more so than age at JAK2V617F acquisition or clonal fraction at diagnosis. Taken together, the key to early detection and prevention may lie in both detecting low burden mutant clones early and in establishing their rate of growth, by repeated sampling, to capture those individuals on a future trajectory to clinical complications. The cornerstone of MPN management currently is aimed at normalising blood counts and reducing risk of thrombotic or haemorrhagic events – such treatments are mostly safe and well-tolerated, and could be offered to individuals with high-risk molecular profiles. Our data also provide a strong rationale for the ongoing evaluation of measures45–48 that target the JAK2V617F clone in order to curb clonal expansion and subsequent clonal evolution (Williams et al 2020)."

REFERENCE

Phylogenetic reconstruction of myeloproliferative neoplasm reveals very early origins and lifelong evolution

Nicholas Williams, Joe Lee, View ORCID ProfileLuiza Moore, E Joanna Baxter, James Hewinson, Kevin J Dawson, Andrew Menzies, Anna L Godfrey, Anthony R Green, Peter J Campbell, View ORCID ProfileJyoti Nangalia

doi: doi.org/10.1101/2020.11.09....

Progression of Myeloproliferative Neoplasms (MPN): Diagnostic and Therapeutic Perspectives

by Julian Baumeister 1,2ORCID,Nicolas Chatain 1,2ORCID,Alexandros Marios Sofias 2,3ORCID,Twan Lammers 2,3ORCID andSteffen Koschmieder

Cells 2021, 10(12), 3551; doi.org/10.3390/cells10123551

[dbus1417]

🤯

[ainslie]

interesting info 👍, I suspect we have had something going on well before diagnosis.

However it’s likely few government health services would screen everyone because of costs, and maybe you need to keep screening them.

It says in the article that the drugs we take are safe etc and they could be given as a preventative, I’m not so sure about that, the current drugs may be safe but we can and do have plenty of problems with them, it’s not like taking vitamins etc. I would be wary about taking the current MPN drugs unless diagnosed. It’s also worth factoring in many people can have Jak2 but never develop a MPN. Maybe as treatments and screening improve but I think it’s a nice ideal but not a practical reality for some time yet.

[socrates_8 in reply to ainslie]

Hey Ainslie...

Thanks for your Post. Yes, my main interest here is acknowledging that our MPN journeys had in fact commenced much earlier (x decades?) than when Dx occurred etc...

Hence, if there was / is anyway to stem the onset by early intervention, it might well be worth greater scrutiny... in my view...

Steve

[saltmarsh]

Very interesting. Thank you. I myself had a TIA 4 years before my PV was diagnosed. I've always wondered although my blood work at the time was normal. 4 years later my platelets were elevated enough to warrant starting this journey.

[socrates_8 in reply to saltmarsh]

Hey Saltmarsh...

Yes, it does make one reflect with our 20/20 MPN hindsight lens does it not?

I also suffered my 1st TIA circa a year prior to Dx. However, I also had many strange symptoms that today I realise are Red Flags for MPN. Had I been treated much earlier for an MPN, I may have averted my 1st very serious TIA paralysis episode, (and more importantly), possibly even prevented having a full blown MPN altogether... possibly! (?)

Whilst this information today doesn't actually aid my ongoing MPN journey a great deal, the continuing research into these findings may well prove that "Prevention" is always better than cure(?)

Best wishes

Steve

[MotanulLink in reply to socrates_8]

I had the same like you , a TIA in 2017, with a lot of tingling in the arms and vision disturbance, (I was dismissed by doctors saying the vision disturbance and headaches as migraines and the tingling as signs of carpal tunnel 🙄 and refused a blood test ) , a TIA in 2021 , then diagnosed with ET in 2022 so it’s been a rollercoaster prior diagnosis and agree probably this was going on for a very long time .

Hopefully now doctors will be more serious and give a blood test early on when the symptoms just start appearing rather then waiting until the disease is fully blown and the body is under so much strain.

Thank you for bringing this up to everyone’s attention, I am going to ask the doctors to test my son as well , just to be sure .

Please keep us updated with any new info.

Many thanks and keep well 🙏🏻

[Mardigras]

Thanks so much for posting Steve.

Hope you are keeping well.

Hugs, Marci

[socrates_8 in reply to Mardigras]

Hey Marci...

Lovely to hear from you too...

Been a while, I too wish all wonderful things for you also...

Best wishes Marci...

Steve

[Meatloaf9]

Interesting. When I was diagnosed in 2017-8 (Dec-Jan) I went back and looked at my old blood test results which I had kept since the 1990's. My Platelets began rising in 2004 and went up by 10 to 20K per year until being diagnosed. So I may have had the MPN for about 10 to 15 years before diagnosis. Originally diagnosed as ET, it became PV in 2021 when my Hct jumped to 55.5% after not having a CBC for 6 months due to rampant COVID in my area and losing several close friends to the disease. Best to all.

[socrates_8]

Hey Meatloaf...

Really sorry to learn that you lost friends during CV 19...

Part of one of the least talked about events of life for me was the day I began to realise that I was not immortal after all, and that we all have our 'use-by dates'.

Hence, I decided to 'Live' the very best way I can...

I too learned many years later that 'High' platelets were a feature of my earlier bloodwork circa 2002. However, I was never alerted to that information... By the time my Dx (2016), I was already experiencing a substantial symptom burden that I had permitted to gradually evolve over many years not ever really knowing anything out of the ordinary was wrong.

In hindsight today, I know that I had many of my symptoms well prior to 2002, however, I will never know exactly how much earlier I suppose...

I've always had a very high body temperature, where others have commented sleeping next to me in winter was like having an electric blanket etc. (Always had cold seats!) Not sure how much earlier I can attribute 'Bone pain' as I was always playing some type of sports, so almost everything was always aching...

But the list goes on & on too...

In my mind, there is very little doubt that my MPN has existed in the shadows for a great many years...

Best wishes Meatloaf...

Steve

[Trocken in reply to socrates_8]

My story is much the same I was diagnosed 6 yrs ago and been reporting similar symptoms, bone pain, fatigue on and off for years, they were always dismissed an eclamptic seizure 12yrs earlier before my daughter was born and then clotting 4 yrs after birth of second child both unexpected and didn’t follow the ‘usual pattern’. I was only diagnosed because a new GP practise looked at my history on my first visit and reviewed my blood work, I’d had a high platelet count for as far back as my digital records show this was 14 yrs of blood work. My platelet count was high (granted only in the 500 -600’s and plummeted to 250 during my pregnancy blood tests. I have the Jak2 gene with low allee burden of 6%. I started treatment a year after diagnosis. Haemotologist are reluctant to treat those of us who are younger as it’s is, due to the life long nature of treatment. I wish my ET had been diagnosed sooner so that I wouldn’t have had the issues I did during child birth that’s for sure. I think we have a long way to go in getting GP’s to look for the signs of those who’s blood work isn’t right before we start looking for genetic mutations in well patients and looking for more sustainable long term treatment options in younger patient groups.

[socrates_8 in reply to Trocken]

Hey there Trocken...

Thanks for your Post reply... Hopefully, we may now be slowly turning that corner into the earlier discovery of MPN Dx(?) Obviously, our own self-advocacy will aid all such progression, in my view... We need to talk with our GPs & ask them for their views on 'How?' earlier awareness of MPNs might be achieved...

Best wishes

Steve

[william-Indo]

Thanks for the post Steve.Wishes you all the best

William

[Luthorville]

Thsnsk for sharing. There are many things that could be tested for as part of a normal blood analysis. Another example that is far more common is celiac. In fact most of the population that has celiac doesn’t even know they have it. If tests were done at volume they would also be cheaper. We tests for all sorts of allergies, it would be interesting to consider testing for all sorts of other conditions by blood.

[EPguy in reply to Luthorville]

I found the inflammatory factors listed in the 2nd report, see my notes, are shared with some of those conditions you note and more. It supports testing of a much larger population, MPNs and many others, for these factors.

[Cja1956]

Great information, as usual. I can’t comment on previous bloodwork before my diagnosis in 2008 at age 52 but I can say that I was diagnosed with Fibromyalgia in my early 30’s. I was teaching back then and I was experiencing terrible weakness, fatigue, and brain fog. I would come home and my husband at the time would have to help me change clothes because of pain in my arms. This was in the late 80’s, early 90’s. My daughter remembers me falling asleep all the time after work. In my 40’s, I was diagnosed with arthritis. So my theory, looking back, is that it was all connected and nobody thought to look at my blood for abnormalities.

[socrates_8 in reply to Cja1956]

Hey Cja...

There seems a multitude of evidentiary pieces to this MPN puzzle... Anything that helps those of future generations learn how better to deal w/ an MPN Dx before it becomes 'full-blown' must be seen as a beneficial & more desirable outcome, in my view ...

Best wishes Cja

Steve

[Cja1956 in reply to socrates_8]

I agree wholeheartedly.

[EPguy]

Some select notes on the 2nd report, it's 2021 so already a bit old. It's consistent with my increasing opinion on the importance of non-drivers:

--

Homozygousity can be progressive, and a reason for VAF increase, with early state being hetoreozy: (both vs only one of the gene pair being mutated) --"Moreover, the progressive loss of heterozygosity and ensuing enhanced mutational allele burden during disease development"

As usual imflammation is a factor. I did a quick search of the factors cited for imflam here, IL-1β, IL-11, HGF, and TGF-β" correlate to many other diseases including inflammatory bowel disease, asthma, and cancer... so chronic inflammation is sort of generic to much disease and MPNs aren't unique there.

One idea to help Dx prefibrotic ET: "Prefibrotic PMF (Pre-PMF), a disease state that mimics ET but shows additional abnormalities in the granulocytic lineage"

I think this refers to the defects found via karyotyping, my report at Dx did karyotyping and none were found in my case matching this note: "chromosomal abnormalities are relatively rare events in ET and PV, they were identified in 46% of PMF [20]. As the acquisition of chromosomal aberrations is a common feature during accelerated and blast phases"

at least two non-drivers really mattered for AML, this does not reference MF progression (TP53 has shown up before as a strong negative prognostic) : "no association was found between JAK2V617F allelic burden and the risk of leukemic progression. Instead, additional factors, such as mutations of TP53 and IDH1/2, were found to correlate with progression to MF and/or AML"

They discuss sensitivities of different mutation tests in this context, if/when our mutations get near 1% regular tests aren't good enough: "A large highly sensitive droplet digital PCR study including 19,958 participants revealed the presence of JAK2V617F and CALR mutations in 3.1% and 0.16%, respectively, of individuals in the general population"

1% may be a cut off for MPN like condition: "a distinct subclinical profile mimicking an MPN phenotype with elevated blood cell counts was observed for individuals with an allelic burden around 1%."

This is in other posts, fibrosis might not be too important: "it is currently unknown whether development of such BM fibrosis is associated with an inferior survival."

How much does v617F matter?, this matches note above AML, are these triple negs positive for one of those non-drivers? (TP53 and IDH1/2) "as most PV patients with a very high allelic burden remain in chronic phase for a long time, while triple-negative MF patients (harboring no JAK2V617F, CALR or MPL mutation) have an elevated risk of leukemic transformation"

Focus on importance of non-drivers for MF: "(TET2, DNMT3A, IDH1/2), transcription factors (TP53, RUNX1, IKZF1), and splicing factors (SF3B1, U2AF1, SRSF2) have been identified and assigned a role in progression from ET or PV to sMF"

Why these are suspect: This is supported by the fact that these mutations are even more frequently mutated in myelodysplastic syndromes (MDS) and AML

IFN may have anti inflammatory advantage over Rux. These are some of the inflam factors(this predates knowledge of Rux's disease modification ability) "While some of the aforementioned cytokines are insensitive to JAK inhibition, IFNa may exert different actions by the repression of IL-1β, IL-11, HGF, and TGF-β"

“Bystander” is a word they use for for “non-driver” mutation and they consistently attribute these with negative prognostic: "Younger PV patients were generally found to harbor a single somatic JAK2V617F mutation, whereas older patients had higher frequencies of bystander mutations [54]. In line with this finding, older patients had a shorter median disease duration until progression to sMF or MPN-BP, although the frequencies were similar."

Detection can be hard. BMB can miss the mutation: "since (a) blood sampling may not contain any traits of the malignant clone, and (b) BM sampling may fail to collect and consequently detect malignant clone hidden “hot-spots”."

They propose non invasive Dx methods including: "MRI is a suitable tool for the evaluation of BM fat content as an indirect correlate of BM cellularity in PMF and potentially ET and PV"

They are not aware of Rux disease modification, this report is 2021, before the new Rux results, and the citation is ancient at 2012 and for MF: "However, to the best of our knowledge, these drugs have minor disease-modifying potential, at least when used as monotherapy, and are not capable of eradicating the malignant clone."

[socrates_8 in reply to EPguy]

Cheers EP guy...

I had previously read through most of the cross ref' but not all...

Best

Steve

[EPguy in reply to socrates_8]

Even some newer reports have not absorbed the new info on Rux. I'm sure it will percolate in time.

Your main item is the long gestation of MPN mutations, I think that is getting well accepted now. Five years ago it was not main stream, thanks for some of why it's getting there.

[socrates_8 in reply to EPguy]

Yes, however, don't dismiss the 'Earlier Detection of MPNs' being a distinct advantage if we can gain that sort of attention in 'Self-advocacy' awareness being shared w/ the general medical fraternity etc.

Cheers EPguy...

Steve

[EPguy in reply to socrates_8]

Agree, knowing that v617f is common and with the ability to measure low alleles it can be tracked through life. It could be the 1% they found to correlate to MPN phenotype may suggest a value at which Tx should be started. As noted in this thread, the two common tx we have that can control VAF do have real risks so slicing that pie needs close consideration. Maybe very low doses of either can cap the allele before it exceeds 1% or other selected limit. The catch is the <1% tests are likely costly.

[socrates_8 in reply to EPguy]

Don't forget that this is inclusive for CALR too...

However, they do not make mention of MPL?

Anyways... looks most promising to me...

Cheers

Steve

[EPguy in reply to socrates_8]

Also missing is triple neg which by definition would be missing. With the 2nd report emphasizing importance "bystander" mutations the next step in early monitoring would be full gene studies. But I'd guess these would need to decline in cost by an order of magnitude to provide for that.