Paper on Misc Mutations

[EPguy]

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Another study:

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

<<Cytokines levels are higher in myelofibrosis compared to PV and ET, with higher IL-2, sIL-2Rα, IL-6 and tumour necrosis factor α (TNFa)>>

NAC supplement improves IL-6, and TNFa in various studies.

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Triple Neg isn't:

<<Previously, a histological diagnosis of an MPN lacking a driver mutation was termed triple negative disease. Advances in sequencing technology have been able to identify novel mutations in JAK2 and MPL reclassifying previously “triple negative” disease>>

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In table 4 non-driver mutations TET2, ASXL1, and TP53 are relatively high in MF.

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ASXL1 is important in leukemia:

<<ASXL1 mutations have significant impacts on prognosis and have been identified in 47% of MPN in the leukemic phase>>

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HU vs allele, molec response is not part of resistance:

<<Whilst European Leukaemia NET (ELN) has a definition for resistance to hydroxyurea, this does not incorporate molecular factors.>>

HU almost never gives prolonged molecular response so everyone would be resistant if that were included.

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On the point of HU resistance etc:

<< ...p53-dependent mechanisms were identified as a resistance mechanism to hydroxyurea in colon cancer cells, highlighting the importance of DNA damage pathways in hydroxyurea sensitivity>>

Dr Golib's statement on risk of Hydrea resistance/tolerance may relate to this p53 path. P53 is quite important and its gene is part of nex gen sequencing.

Rux is less likely to work with high risk mutations:

<<Clinical data reveal that response to JAK2 inhibition is impaired with concurrent ASXL1 and EZH2 mutations (hazards ratio of 2.94) and that 3 or more high molecular risk mutations have a shorter time to treatment failure>>

This has been a topic of other threads.

Fedratinib is recently approved Jak inhibitor:

<<The degree of immunosuppression appears less due to its selectivity for JAK2>>

It might be better for vax response and disease resistance, although this is likely a 2ndary issue if it is prescribed.

INF goes after both good and bad Jak2 cells but kills more bad ones:

<<Treatment with IFNα stimulates both JAK2V617F-positive and WT quiescent stem cells into cycle but leads to a preferential depletion of JAK2V617F>>

Bad mutations for INF response:

<<Concomitant TET2 or DNMT3A mutations are associated with molecular resistance to interferon [200]. The FIM study also showed inferior response to IFNα in patients with high molecular risk (HMR) mutations (defined as ASXL1, SRSF2, EZH2 and IDH1/2)>>

I've seen that DNMT3A can emerge during INF treatment so a genetic test during treatment might be useful for some.

[Meatloaf9]

Hi, the MPN research foundation is sponsoring the Interferon Initiative. A recent newsletter said that their pre clinical studies did not find that the DNMT3A mutation was resistant to interferon. Hoping that is correct as I have that mutation. I guess we have to wait on the clinical studies to find out for sure. My MPN specialist said that the jury was still out on this. Who knows?

[EPguy in reply to Meatloaf9]

That would be very good result, if it does not inhibit INF and does not emerge with INF.

I have seen the INF initiative. Since INF takes time I expect any actionable results will be a while.

The other one we will look fwd to is Mithridate, this should have the most solid results for INF, HU, and Rux, but not till late this decade.

[Meatloaf9 in reply to EPguy]

Thank you for all your posts and information. Please continue to do so. Best always.