New! advances in the role of JAK2 V617F mutation in myeloproliferative neoplasms (MPN)

[Elizka]

Hello,

I purchased this white paper, but not sure I can share online. If you send me a message, I'll forward you the PDF. Here is the summary online: acsjournals.onlinelibrary.w...

After reading this paper, I'm going to take a more aggressive approach to my cardiac health. I might even consider a second medication along with Besremi and perhaps a statin. I'm also updating my supplement list.

Any ideas on other "integrated therapeutic strategies"?

Here is a more detailed summary:

The white paper titled "New advances in the role of JAK2 V617F mutation in myeloproliferative neoplasms (MPN)" explores the pivotal role of the JAK2 V617F mutation in the development, progression, and treatment challenges of MPN. Here's a summarized overview:

Key Highlights:

JAK2 V617F Mutation Overview:

Found in 95% of polycythemia vera (PV), 50-70% of essential thrombocythemia (ET), and 40-50% of primary myelofibrosis (PMF) cases.

It drives persistent activation of the JAK/STAT pathway, leading to uncontrolled cell proliferation, differentiation, and survival.

Mechanisms Beyond JAK/STAT:

Activates non-JAK/STAT pathways (PI3K/AKT/mTOR, MAPK) contributing to tumorigenesis and resistance to JAK inhibitors.

Alters epigenetic regulation, including DNA and histone methylation, impacting gene expression and cellular functions.

Impact on DNA Damage and Repair:

Promotes DNA damage accumulation by impairing apoptosis and checkpoint functions.

Inhibits key tumor suppressors (e.g., p53) and DNA repair mechanisms, contributing to genetic instability and disease progression.

Cardiovascular Complications:

Increases the risk of arterial thrombosis, atherosclerosis, and cardiac hypertrophy.

Affects blood cell properties and endothelial cell functions, exacerbating thrombotic tendencies and vessel damage.

Therapeutic Insights:

While JAK inhibitors alleviate symptoms, they cannot eradicate the mutant clones or halt disease progression.

The paper advocates for combination therapies targeting epigenetic modifiers, non-JAK/STAT pathways, and immune evasion mechanisms.

Future Directions:

Calls for deeper understanding of JAK2 V617F's broader effects to identify novel therapeutic targets.

Emphasizes the need for personalized, multidrug approaches to improve outcomes and address the unmet need for curative treatments.

Conclusion:

The JAK2 V617F mutation is central to the pathogenesis of MPN, influencing hematologic and cardiovascular systems through diverse mechanisms. Current treatments, focused primarily on JAK inhibition, fall short of curative potential, highlighting the importance of integrated therapeutic strategies to manage and eventually overcome MPN.

✋END:

✔️Here is what ChatGBT suggested when I asked for integrated therapeutic strategies based on the research. Obviously this not medical advice:

The paper emphasizes integrated therapeutic strategies as a promising approach to address the limitations of current treatments for myeloproliferative neoplasms (MPNs), particularly those driven by the JAK2 V617F mutation.

Key suggestions include:

1. Combination Therapies:

JAK Inhibitors + Non-JAK/STAT Pathway Targets:

Combining JAK inhibitors with drugs targeting pathways like PI3K/AKT/mTOR, MAPK, or others could improve therapeutic efficacy by tackling compensatory survival mechanisms that sustain mutant cells.

Epigenetic Modifiers:

Agents like decitabine (a DNA methyltransferase inhibitor) may work synergistically with JAK inhibitors by altering epigenetic dysregulation, such as DNA or histone methylation, caused by the JAK2 V617F mutation.

HIF-1α Inhibitors:

Blocking hypoxia-inducible factor 1α (HIF-1α), which is upregulated in JAK2 V617F-positive cells, could suppress cell proliferation and enhance treatment outcomes.

2. Targeting DNA Damage and Repair:

Therapies designed to:

Enhance apoptosis in JAK2 V617F-positive cells by overcoming DNA damage repair mechanisms that the mutation disrupts.

Inhibit key players like RAD51 or promote p53 activation to restore the normal DNA damage response.

3. Cardiovascular Risk Management:

Statins: To reduce oxidative stress and improve endothelial function.

Antithrombotic therapies such as:

Aspirin: To lower platelet aggregation and thrombosis risk.

Interventions targeting neutrophil extracellular trap (NET) formation, which contributes to thrombosis.

4. Immune Modulation:

Targeting immune evasion pathways, such as the PD-L1/PD-1 axis, to prevent JAK2 V617F-positive cells from escaping immune surveillance.

Using interferon-alpha (IFNα) to stimulate immune responses against mutant clones.

5. New Epigenetic and Protein Targets:

Targeting epigenetic regulators (e.g., PRMT5, TET2, DNMT3A) or chromatin-modifying enzymes involved in maintaining mutant cell survival.

Focusing on proteins essential for JAK2 V617F-positive cell viability, such as JMJD2C or NFE2.

6. Tailored Approaches for Specific Pathways:

Investigating drugs that selectively inhibit mutant JAK2-driven signaling without affecting normal cells.

Exploring agents that alter cytokine receptor interactions or reduce aberrant cytokine receptor recycling, such as therapies affecting thrombopoietin receptor (TPOR) pathways.

7. Personalized Medicine:

Stratifying patients based on their mutation burden, subtype (e.g., PV, ET, PMF), and molecular profiles to customize therapeutic combinations.

8. Research and Experimental Therapies:

Encouraging ongoing research into novel pathways activated by the JAK2 V617F mutation to identify additional drug targets.

Testing experimental drugs in combination with JAK inhibitors in preclinical and clinical settings to determine synergistic effects.

[Mostew]

Thank you for above . Great summery. It was enough for my un academic brain!

[Nan14]

Thank you for sharing. I'd be interested to read the full article if you can share. I am new on this journey and want to be sure all treatment now and in the future is suitable for me.

[RoundTheWorld in reply to Nan14]

Nan14 - I meant to say hello earlier. I’m similar age to you and diagnosed last May. This forum has helped me a lot (and the main MPN Voice website).

[Nan14 in reply to RoundTheWorld]

Hi, thanks for reaching out.How are you coping with the diagnosis?

I have signed up to MPN voice also and have the App with a linked health watch so I can log my symptoms and the team from Guys researching this disease and follow and track changes. I did opt out of the watch but they sent it in error, so i decided to try it! It's a great motivator to get moving. I'm happy to share more info if you want, but won't bore you on that.

I have learnt so much since my GP alerted me to the fact I needed further investigations because my RBC was so high.

From the point of a confirmed diagnosis until Christmas was a bit of a blurr, my bloods have been stable for a few weeks so I'm hoping I can be managed with occasional venesections and asprin for years to come.

[RoundTheWorld in reply to Nan14]

It has taken time but I’m getting there! So many questions and few answers at first. Finding the people here and MPN Voice have really helped .

[DougyW in reply to Nan14]

Hi Nan, it pays to have some knowledge for yourself so you can self advocate. In the UK most haemologists are not knowledgeable so just look to the traditional approaches. Hope your journey is smooth & long.

[Bluetop]

Many thanks for sharing. I would be interested in reading the full article if there is a way of sharing.

[rmfisch]

thanks so much Elizka. I too would love to see the article if you are able to share

[EPguy]

Good to see the ideas for combo therapies. There are in fact a number of such going on right now, these trial include some with Rux combos. I have not checked whether any are those in this report, but trials all start with reports just like the one you helpfully provide us here.

clinicaltrials.gov/search?c...

Is there a mention of the three new drugs that tightly target Jak2? , discussed in various prior posts. All are in ph 1 trials, two for MF which target v617f precisely and another, one for PV with FDA breakthru status that targets just Jak2 in possibly a new way, (vs intentionally both Jak1+2 for Rux)

--

One item that often still appears in reports is no longer current: "While JAK inhibitors alleviate symptoms, they cannot eradicate the mutant clones or halt disease progression."

The category of Rux, a Jak "inhibitor" does not suggest capacity for a "reducer". But likely via some of its indirect immune effects not known in its earlier use, it is both inhibitor and reducer. Two recent studies, in various posts, showed precisely these positive outcomes and a correlation between them. Also members here are reporting VAF reductions.

[Elizka in reply to EPguy]

While the white paper recognizes the importance of interferon-alpha in managing MPNs, particularly its ability to reduce mutant clones, it frames it as one part of a broader therapeutic strategy. But Besremi is a disease-modifying therapy that targets the root cause of MPNs, with the potential to reduce or eliminate mutant cells. If your VAF is below 10% why would taking Jakfafi for instance be helpful? I was somewhat confused on combination therapy suggestions.

Other drugs mentioned:

1. Next-Generation JAK2 Inhibitors

Selective JAK2 Inhibitors: Researchers are developing inhibitors that specifically target the JAK2 V617F mutation to minimize effects on normal cells. For instance, structural studies have identified compounds that bind uniquely to the mutated JAK2, potentially offering more precise inhibition.

AACR JOURNALS

Type II and Pseudokinase Inhibitors: Compounds like BBT594 and CHZ868 (Type II inhibitors) and JNJ7706621 (pseudokinase inhibitor) are under investigation. These aim to inhibit JAK2 by binding to different conformations or domains of the enzyme, potentially overcoming resistance seen with current therapies.

AACR JOURNALS

2. Combination Therapies

Triple-Drug Regimens: Recent clinical trials have explored combinations of existing drugs to enhance treatment efficacy. For example, a study combining Revumenib, Venetoclax, and Inqovi showed promising results in patients with relapsed or refractory acute myeloid leukemia, achieving high remission rates.

REUTERS

3. Epigenetic Modulators

Menin Inhibitors: Drugs like Revumenib target the interaction between menin and other proteins involved in gene expression. By disrupting this interaction, these inhibitors can potentially reverse abnormal gene expression patterns associated with MPNs.

REUTERS

[EPguy in reply to Elizka]

This text from the report "If your VAF is below 10% why would taking Jakfafi for instance be helpful? " is strange. Do you have more context to it? I started Rux at 7% VAF and lower VAF is generally desirable for any reference level.

" Besremi is a disease-modifying therapy that targets the root cause of MPNs," do they offer root causes beyond Jak2? Some researchers are hard at work on this question.

1. Next-Generation JAK2 Inhibitors:

INCB160058 and AJ1-11095 are two current ones. There is a third also, VGT-1849A. Manouche has posted on these and I've added comments. These are promising agents.

"BBT594 and CHZ868 (Type II inhibitors)" were duds from what I can tell and have posted. The latest type 2's seem more promising.

JNJ7706621 has links from 2005, maybe it's being revived to MPNs but search results are slim.

[RoundTheWorld]

Btw there’s discussion of combined therapy research and also of statins in the post ASH video Mazcd posted yesterday.

[Elizka in reply to RoundTheWorld]

Thank you. I iwill check it out. I wanted to talk a statin, but I already take Rephata not for elevated cholesterol, but lipoprotein (a). Not sure I can take two.

[Elizka in reply to RoundTheWorld]

I can't seem to find the video?

[RoundTheWorld in reply to Elizka]

You can find it on the MPN Voice YouTube page (not sure if I’m allowed to add the link here or not).