Impaired tumor surveillance in JAK2V617F MPN

[Manouche]

 »In conclusion, our findings suggest that Natural Killer cells have an immature profile with deficient cytotoxicity that may lead to impaired tumor surveillance in MPN. These data provide a new perspective on the behavior of NK cells in the context of myeloid malignancies and can contribute to the development of new therapeutic strategies, targeting onco-inflammatory pathways that can potentially control transformed HSCs. »

frontiersin.org/articles/10...

[EPguy]

Their results seem to show complex and not easy-to-read nor consistent (for this non-expert) effects on NK functions. But one consistent finding is the NKs are immature in MPNs, consistent with the section from your summary:

"the maturation arrest here found may favor MPN progression due to uncontrolled expansion of the neoplastic HSC..."

So if I see an actionable result of this info it would be to find ways to help NKs become mature in us, but this study does not extend to that area.

An interesting note on Jak inhibitors, noting as is now known that Jaki's don't get to the deep source of MPN. LSC is leukemic stem cell, which is a bit confusing since that I believe is specific to blast phase, AML type disease. I think they refer more generally to MPN condition:

"Although useful to target the disease phenotype, the failure of JAK2 pharmacological inhibitors to eliminate LSC in BCR-ABL1-negative MPN suggests that targeting other elements associated with MPN pathogenesis is crucial"

The idea with IFN is to target some of that "other".

[FG251]

Aren’t interferons meant to restore tumor surveillance?

[Manouche in reply to FG251]

One of the mechanisms of action of IFN-alpha2 involves stimulation of immune cells, not tumor surveillance as such.

[FG251 in reply to Manouche]

I found this, in an article by Dr Hasselbalch.

Tumor surveillance

[Manouche in reply to FG251]

Interferons do not have a direct action on tumor surveillance, but they potentially restore the capacity of some immune cells to do the job properly.

[EPguy in reply to Manouche]

I know this is over my head, but curious to look some.

-In sum, it seems IFN forces damage to otherwise hidden Jak2's by stirring things up, but mutant ones fail faster once stirred.

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

Normal marrow stem cells (HSC) stay quiet, unless and until something requires action like infection or chronic blood loss. Then they wake and produce blood cells or more stem cells. It seems mutant ones also stay relatively quiet at least in this context.

In several reports, IFN causes HSC to exit this quiet (quiescence) state and become active without natural causes like infection etc. Both normal (wild type, WT) and mutated Jak2 (v617f) are stimulated this way. But the v617f ones get more DNA damage once they wake up and thus die out faster than WT cells. So we need to lose both good and bad Jak2's to be rid of the bad:

"peg-IFN-α treated Jak2+/VF LT-HSCs (mutant Jak2s) showed greater reduction in quiescence and greater accumulation in G1 phase (a growth stage in cells, G0 is no action) , higher ROS (oxidation stress) production and more DNA damage compared with peg-IFN-α treated WT LT-HSCs"

So the good jak2s activate but the bad ones go nuts and wear out.

In this report immune response is not a focus, no doubt there is a lot of action there too.

This report also has a good quality comparison of Rux and IFN for allele reduction with the note "patients with JAK2V617F show only minor reductions in mutant allelic burden, even after long-term treatment, suggesting that ruxolitinib is unable to eradicate MPN disease-initiating cells." I've seen this in other reports, Rux can reduce allele but not as often nor as much on average. Their intent is to contrast this result with IFN.

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They cited this one, which supports that forcing HSCs to wake up damages all types, this is in context of getting old normally:

"Repeated activation of HSCs out of their dormant state provoked the attrition of normal HSCs"

pubmed.ncbi.nlm.nih.gov/257...

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Other reports suggest the old non-Peg IFN stirred things up too often and the HSCs eventually stopped waking up, but PEG IFN gives enough time between doses for recovery and fresh HSC waking. This would support longer dose intervals if we have the option.

[DiveGoddess]

I want to understand this. Newly diagnosed. ET. Thank you post, I going to read article, but if you can dumb it down, I certainly would be grateful 😊