Exciting News from the MPN Research Foundation for us Jak2'ers

[Hello94]

mpnresearchfoundation.org/n...

[EPguy]

Neat progress. It seems there was some work ~2018 on this area and not much again till now. It's all about integrin, a seemingly new target for MPNs.

jci.org/articles/view/123388

"Whether targeting β1 and β2 integrin activation as a means of preventing thrombosis in MPNs is a viable strategy merits further exploration."

It seems Dr Matsuura is planning this follow up.

"One outstanding question not addressed in this study is whether inhibition of JAK2 with agents, such as ruxolitinib, might impact β1 and β2 integrin activation driven by mutant JAK2"

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Looking into that Rux question, it seems Rux may be active against integrin. This is obscure stuff over my head but here seems to be something, but this study is in vitro only (not in creatures)

"Pharmacological inhibition (Via Jak-i) of JAK2-V617F downregulated sVCAM1 binding in a time-dependent fashion"

sVCAM1 binding is the bad thing integrin does with Jak2 v617f.

In this plot, the bar chart shows using Jak-i (the + sign via Rux for example) way cuts the blue bar mutant level. - sign was inactive control treatment.

So maybe Rux reduces Jak2 VAF by the integrin route.

nature.com/articles/leu201726

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Here is likely the mouse study the MPN research article refers:

pubmed.ncbi.nlm.nih.gov/300...

And reference to the same VCAM1 agents: "...VCAM and ICAM1 ligand binding assays revealed increased affinity of β1 and β2 integrins..."

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Let's hope the new research improves or helps further on Rux for this new target.

VAF vs Integrin Binding, Jak-i effect

[KLCTJC in reply to EPguy]

I hope you are doing well. Reading your post and reading this article. To be honest despite my background of being in medicine some of this pathophysiology goes way over my head. But I just think it is still interesting to see beta 1 & beta 2 mentioned. As you know I am the weirdo with MS too. And every time I look through stuff I am always looking for key words that catch my eye. Even though I may not understand everything! Just appreciate you. And so glad Rux is working out for you. Didn’t know if you knew they have a topical version of that exact medication and I prescribe it mostly for vitiligo. And it is doing amazing! I am going to help in a trial in the fall for vitiligo patients and I am so excited! I love the thought of being able to change these peoples lives. So JAK inhibitors are doing so many amazing things these days! I thank god everyday for modern medicine and pray if by chance my daughter gets any of this they will just be able to fix it! Again good to hear from you!!!!

[EPguy in reply to KLCTJC]

I am familiar with the topical, it's "OPZELURA" is that right? It has a black box warning while so far oral Rux does not (yet)

That's neat to be working with a trial.

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I agree this deep level on integrins is for post grads to earn their advancement. I don't feel a need to u'stand these details any more than I do an automatic transmission. (I did recently rebuild a manual for my MG but auto is a whole other game) But I look for patterns and these various reports seem to fit.

A quick look at a term in Manouches reply "nintedanib" this comes up:

pubmed.ncbi.nlm.nih.gov/370...

"This case shows the potential of combination treatment with JAKi and nintedanib for the prevention of worsening of disease activity in RA and ILD." (rheumatoid arthritis with progressive interstitial lung disease)

So Jak-i added to nintedanib could maybe help MPN too.

I care directly about ILD since my Sjogren's details put me at risk for it. I'm glad to be on Rux right now.

[KLCTJC in reply to EPguy]

It is!! And yes to the black box warning which isn’t for oral version. But it is the black box warning for all other oral jaks we use in dermatology right now but difference is things like rinvoq block 1,2, and 3. I think fda insisted on it. Other drug I prescribe all the time that has this for a topical is protopic and elidel. I am not going to say anything on any of these as I know clinical practice results not always down to the letter clinical trials. But I don’t think any of that stuff was in the clinical trial. I am excited to help out one of my physicians with a clinical trial as I have never helped with one. Will be something new after 15 years.

I am just so glad to see your post. And these new meds even though I may not understand all the details! Especially despite our different diseases I still think there is a link between autoimmune and MPNs. And last time I posted something that wasn’t back up to the letter someone got upset. (So please, only my theory, maybe no science). I am glad we both just seem to be doing ok.

And I know nothing about cars except where to push start these days!! But good to know I have someone out there I could ask.

[Manouche in reply to EPguy]

 »Integrins are **transmembrane receptors** that mediate cell-cell and cell-extracellular matrix (ECM) adhesion². According to some studies, there is a relation between integrins and MPNs, as integrins can regulate the survival, proliferation and migration of hematopoietic stem cells (HSCs), which are the source of blood cells. Some integrins, such as **α4β1** and **α5β1**, have been shown to be involved in the pathogenesis of MPNs by promoting the interaction of HSCs with the bone marrow niche . Moreover, some drugs that target integrins, such as **cilengitide** and **nintedanib**, have been tested as potential therapies for MPNs, with mixed results . Therefore, integrins and MPNs have a complex and dynamic relation that is still being investigated »

(1) Integrin - Wikipedia. en.wikipedia.org/wiki/Integrin.

(2) Integrins - Molecular Biology of the Cell - NCBI Bookshelf. ncbi.nlm.nih.gov/books/NBK2....

(3) Integrins: An Overview of Structural and Functional Aspects. ncbi.nlm.nih.gov/books/NBK6....

[PhysAssist in reply to Manouche]

Hi Manouche,

As an aside:

Am I the only one who found it odd/interesting that her medical credentials are in veterinary medicine?

Regardless, I hope her work eventually pays off for some [or better yet all] of us.

Best,

PA

[saltmarsh]

Thanks for the post. Much appreciated

[PhysAssist]

Hi Hello94,

Great post and thanks for the link.

Thanks for the comments and insights from Hunter, Manouche, and EPguy also!

The article seems generally pretty vague in it's understanding of MPN's, but that's probably due to the author/editor's lack of understanding and is clearly not attributable to Dr. Matsuura.

I followed her name links and found this editorial article from her and a co-author that I thought was interesting:

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

There was also this article which may [to some one with more active brain cells than myself] give further insight into the role and activity of Integrins:

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

Thanks again, and best regards always,

PA