Anyone familiar with DNMT3A?

[Dan39]

Hi everyone, hope all is well with everyone! Btw some updates about my mpn, I’ve just got my results from NGS test recently, as a result got my jak2 and DNMT3A positive, so now I’m confirmed primary myelofibrosis and 5 days ago I’ve gone through routine endoscopy (as a result ligation in several spots) and after 4 months without ligation due to my previous total blockage in my vena porta, anyway is there anyone familiar with DNMT3A? Variant-Specific Information:

DNMT3A:chr2(GRCh37):g.25467164C>G;

NM_022552(DNMT3A):c.1711G>C; p.Ala571Pro (16% VAF)

[hunter5582]

Suggest reviewing the significance of the DNMT3A mutation with your care team. The JAK2 mutation is the driver mutation. DNMT3A is a known non-driver mutation that is involved in MPN progression. I also have a non-driver mutation in addition to JAK2. in my case it is a germline NF1 mutation that also causes another medical condition. The understanding of the role of these non-driver mutations is emerging. The presence of non-driver mutations can impact how you think about risk of progression and treatment.

Hopefully you already have a MPN Specialist on your care team (not a regular hematologist). This specialist would do the best job explaining the significance of your genetic profile.

Please let us know what you learn and how you get on.

[Wyebird in reply to hunter5582]

I’m in awe of your knowledge Hunter

[Dan39 in reply to hunter5582]

Thankss for the tip top answer, you’re one of my fave’s person if I’m seeking for an answer.. GBU Hunter!

[EPguy]

As hunter says, your MPN team can give you the best info. It's good your team is MPN savvy and ordered this test.

There is some info in this post. It's not easy reading but it might give you a start for questions for your team.

healthunlocked.com/mpnvoice...

[Dan39 in reply to EPguy]

Thanks for the update! GBU epguy!

[EPguy in reply to Dan39]

A few items from the report that I linked below for easier reference: (this is only one study, but a detailed one)

I'm on INF (Besremi) so I may ask for a full gene sequence again at some point to check my DNMT3A status. I started with none detected.

---

-INF therapy causes a small increase in odds of getting or increasing this mutation, more than with HU.

-TET2, DNMT3A, or ASXL1 associate with older age and major thrombosis and esp prior stroke (odds ratio 5.2) this is very strong correlation when both age and these mutations are present. This is generally consistent with the notes from Meatloaf9 here.

-DNMT3A is most associated with non-CHR (not achieving complete blood response)

-DMT3A remains functional- << the majority of DNMT3A mutations found in MPN (and in this study) are heterozygous missense mutations that do not result in complete loss of DNMT3A function>>

-Broken DNMT3A leads to more broken Jak2 <<Dnmt3a loss induced aberrant self-renewal of Jak2-mutant hematopoietic stem cells>> Maybe something to do with the non-CHR?

[Wyebird]

Hi wow I’ve just read Hunter5582 reply. It’s so precise. Hope all goes well when you discuss results with your heamo.

[Dan39 in reply to Wyebird]

Same goes to you Wyebird! GBU

[robbjoy]

DNMT3A at 6.8% occurrence is the 8th most common MPN mutation ghr.nlm.nih.gov/gene/DNMT3A

Here is a detailed listing of primary and the common secondary mutations and their meaning:

mpnjournal.org/?fbclid=IwAR...

medlineplus.gov/genetics/ge...

[Dan39 in reply to robbjoy]

Thanks for the info robbjoy! GBU

[SoledadBarcelona]

I know a few things about it, but my hematologist dosent care. This is a novo gen, it means that you was born with it and your lifestyle woke up it. This is a gene of the DNA methylation and the epigenetic part. This is an epigenetic mark that plays an essential role in regulador gene expression.

What do you have to do? Change your mind , follow a healthy healthy and healthy lifestyle with diet, no alcohol, no tobacco, exercise to keep in shape your genes, no toxics, vitamine people and no toxics ones, maybe any kind of suplementation (before checking your levels of zinc, magnesium, calcio, vitamine D, Omega 3 how the most important).

Let us know what your hematologist says.

Thanks

[Dan39 in reply to SoledadBarcelona]

Great advice soledadbarcelona! I will keep you posted, next month my appointment with my Mpnspecialist in Singapore and I will keep you posted! GBU

[Meatloaf9]

I am familiar with DNMT3A to the extent that I have that mutation. Tested positive in 2018. When I ask my MPN specialist at Cleveland Clinic he keeps telling me that the jury is still out on it and they do not know precisely how it affects mpn patients. He says that more studies are needed. I did read a scientific article that said this mutation conferred a poorer prognosis for people who have a MI. They apparently do not do as well after the heart attack as those who do not have this mutation. That article was about cardiovascular disease.

Best to you.

[Dan39 in reply to Meatloaf9]

Thanks meatloaf9! I hope we will be fine and everyone too! Currently im PMF intermidiate but wait and see (sounds hanging to me but hope for the best) All the very best to you too! GBU!

[SoledadBarcelona]

Dan39 and Meatloaf9. A paper very interesting. It is true the hematologists dont know too much about it, but if you have the opportunity ask for information to a integrative doctor.

Dan39, I forgot: taking care of your microbiote. This is the strong point too.

ashpublications.org/blood/a...

[Meatloaf9 in reply to SoledadBarcelona]

Thank you for posting this article, I am going to take it with me in July when I see my mpn specialist. I wish I understood more of it than I do, such as what is a double mutant mouse?I am glad to see that on the scoring system that dnmt3a is not considered a high risk mutation in humans. I guess mice are not as lucky. When I asked my mpn specialist about a year ago about a study that was done in mice concerning progression to mf and vitamin D he only commented that "they have cured leukemia many times in mice but it did not translate to humans" so my guy doesn't put a lot of faith in mice studies, I hope he is right. I don't know.

Thanks for posting this article and best to you always.

[TLJ-1 in reply to Meatloaf9]

Well, Meatloaf9, I didn't read that particular paper, but it would be possible for researchers to knock-in or knock-out genes in a mouse such that the mouse would express a mutant protein for CALR or JAK2 or MPL, as a driver mutation for MPNs, as well as a mutation for one of the non-driver mutations (e.g., ASXL1 or DNMT3A) as a "double-mutant) model to monitor the effects of these non-drivers on any measurables they might want to measure (e.g., survival, spleen size, etc).

As noted, there are differences, yet still similarities, between humans and mice. For this reason, the researchers typically try to see if the mutant mice have any "symptoms" that mimic those in humans (e.g., spleen size, fibrosis, blood counts, etc).

[EPguy in reply to Meatloaf9]

A quick read, double mutant seems to refer to having both Jak2V617F and Dnmt3a vs only Jak2V617F.

They noted that the mice were forcibly given the dmnt3a mutation after having Jak2, while MPN humans get it naturally before getting Jak2. So the order and way of acquisition is different and the results thus may be different.

I agree many studies have had lucky mice, but the human studies do need to start somewhere.

[Meatloaf9 in reply to EPguy]

Thank you for the clarification. I absolutely agree that the research has to start somewhere. The takeaway I got from my Doc on the article about Vit D leading to an increased chance or maybe it said cause of MF in mice was that it did not necessarily mean that taking high doses of Vit D would necessarily lead to the same result (MF) in humans. We had that discussion because it was reported that those with high levels of Vit D might have some protection against contracting Covid. I wanted to know if I should try to get my Vit D level high as a possible deterrent to Covid but was worried about the possibility of increasing the chance of MF. I hope that the researchers keep researching until a cure is found for these mpn's as well as every other disease. I am confident they will find cures for these diseases just don't know when it will happen.Thanks for posting.

Best to you always.

[EPguy in reply to Meatloaf9]

I don't know much about the Vit D results, but from your description it seems patients had hi vit D rather than took pills to get it. So maybe other interactions in the body have vit D as a side effect while these same interactions separately cause the MF correlation.

My Vit D is not low, being a resident of sunny So Calif...