Hereditary MPNs -debunking some myths

[TTA_]

As someone was declaring with a bit of overconfidence that MPNs are not hereditary, it is good to debunk several myths related to hereditary MPNs.

1. There are hereditary MPNs. Not as many as familial MPNs, but there are hereditary MPNs. pmc.ncbi.nlm.nih.gov/articl...

The mutations causing hereditary MPNs are called germline. Unlike the somatic mutations that cause most of the MPNs, mutations that can be found only in the affected cells, i.e. in blood and bone marrow, pathogenic germline mutations that cause MPNs are transmitted from parents to children and can be found in the DNA of every cell in your body. In familial MPNs, one inherits the propensity to acquire a pathogenic mutation during their lifetime that could lead to MPNs. Said mutation is often the same as in sporadic MPNs, a somatic mutation (e.g, JAK2V617F or MPL W515K/L). In hereditary MPNs, one inherits the respective mutation from their parents like one inherits eye colour. Having a germline mutation does not mean one would necessarily manifest signs of MPNs, though. Some people will have the disease, other people will not, despite having the germline mutation.

There are different mutations that can cause hereditary thrombocytosis, some on JAK2 gene, but much more on MPL, and other genes. TPO is another gene on which pathogenic germline mutations can cause hereditary thrombocytosis.

If you want to learn more about hereditary MPNs, the studies below presents some of these germline mutations that can cause them:

ashpublications.org/blood/a...

pubmed.ncbi.nlm.nih.gov/325...

There was a dogma in the past that MPNs are never hereditary, which contributed to hereditary MPNs being understudied. We should not reinforce said dogma. It has done enough harm. There are few studies on hereditary MPNs, and for hereditary thrombocytosis there is barely any guideline on diagnosis and treatment.

2. There was this other myth that hereditary thrombocytosis never transforms into myelofibrosis or AML, yet studies show that hereditary thrombocytosis can and does transform into myelofibrosis and AML. This is understudied, and the dogma that hereditary MPNs are somehow benign might have contributed to this. The studies that exist do show that hereditary thrombocytosis does transform into myelofibrosis and even AML. Given how many germline mutations there are that can cause hereditary MPNs, transformation might depend on the type of mutation, but also on other factors.

pmc.ncbi.nlm.nih.gov/articl...

ashpublications.org/blood/a...

I hope more awareness will be raised and more research will be done in the field of both familial MPNs and in the field of hereditary MPNs.

[hunter5582]

Thanks for posting the links. I just added some on the Familial MPN thread that you responded to.

I think that the evidence is clear that patterns of inheritance play a role in classic MPNs as well as Inherited Erythrocytosis and Thrombocytosis. This is not understood as well as it needs to be. The involved genetics are complex and need further investigation to better understand how the patterns of inheritance work.

There are some in the medical community that are not up to date on this emerging science. This is unfortunate as it leads to misinformation being relayed. I suspect that many cases of Familial MPNs and the other inherited variants have gone undetected for a long time due to this lack of awareness.

At the same time, we need to not panic that the myeloproliferative disorders will automatically be passed on. It is more complex than that. It also depends on what form the genetic variant takes. You correctly identify the difference between a germline and somatic mutation. In addition, germline mutations can be autosomal dominant , recessive, incomplete dominant or codominant. There is even more complexity to the genetics involved than this. There is plenty to learn to fully understand.

I agree that more awareness is needed regarding the genetics of Familial MPNs and the Inherited myeloproliferative disorders. It is also important to understand why there seem to be clusters attached of other blood cancers like lymphoma. One avenue worth investigating has to do with the role of inherited telomere abnormalities. pmc.ncbi.nlm.nih.gov/articl...

There is much to learn. We can support the research that is needed through our advocacy and willingness to participate in the research.

All the best.

[Fairydust1111]

thank you so much TTA, very informative and very interesting indeed! Thanking you and I hope you are keeping well

[Spanelmad]

Great information thankyou

[JediReject]

It's not before time that some serious research was done because I long suspected there are familial links. When I was diagnosed in 2006 I asked the question of my then consultant who had a very good reputation in Haematology but he categorically stated it was simply bad luck and that was why it was called Idiopathic. I pointed out my Grand-Mother had some type of Leukemia / blood cancer (died in 1950s before I was born) my Mother had died of Myeloma, a cousin who wasn't local to me and I didn't have contact with also had a type of blood cancer. But he simply dismissed it all with a smile and said he was sorry but I was just unlucky in life's lottery.

I know it's cropped up several times on the Forum over the years and there's a raft of anecdotal evidence so I'm pleased that finally it's on the agenda and some dedicated folk are hopefully delving deep into the subject which in the future might help identify those at risk and more if they utilise AI 😲 (you never know).

Regards - Chris

[nellietheelephamt]

Yes, I asked about "inherited" bone marrow and blood diseases back when I was diagnosed with erythrocytosis as my maternal family line is littered with examples but was told there was no evidence.

Had I been taken more seriously or attended a more major hospital perhaps the investigation would have stated earlier.

How times change.

[S031251]

My sister passed away aged 69 this year / she had Waldenstroms (non Hodgkin’s lymphoma. I have PV,

Anna

[mhos61]

I placed a post on this topic eight years ago. I had joined this forum the previous year and was taken aback by a fair amount of members who had more than one person in their family with an MPN.

I don’t know if there is any connection, but my first cousin had ‘Non Hodgkins Lymphoma’ successfully treated. However, why I placed the post was my Father died in his early forties of a heart attack (no family history) and it did make me wonder if there was a possibility he had an undiagnosed MPN.

Thanks for this!

[SDJD in reply to mhos61]

I have ET and my brother has Non Hodgkins Lymphoma. I think there are quite a few of us MPN patients who have relatives with blood cancers. Interesting!

[Bluetop]

Thanks for posting. Some interesting work to pour over.