JAK2 Reversible Activation Shows an Essential Requirement for Jak2V617F in MPN

[Manouche]

 « We hypothesized that the limited potency of JAK inhibition relates to insufficient mutant kinase inhibition at achievable therapeutic doses, and we and others have elucidated mechanisms by which mutant JAK2 can signal in the presence of type I JAK inhibitors »

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These data support the notion that improved targeting of JAK2 signaling and downstream effectors offers greater therapeutic potential than current JAK kinase inhibitors and that JAK2V617F mutant-selective inhibition represents a potential curative strategy for the treatment of MPN patients. »

biorxiv.org/content/10.1101...

[Aneliv9]

I didn't understand much! Could you please write a small simple summary?😀

[Manouche in reply to Aneliv9]

The authors remains “believers” that JAK2 represents the best therapeutic target in MPN, and have used genetic and pharmacologic (tool type II inhibitors) to suggest that MPN cells remain JAK2 dependent. But they could never prove this for JAK2V617F in vivo. This is now proven.

[Aneliv9 in reply to Manouche]

So this study suggests that a possible cure is only when someone has the jak2 mutation?

[EPguy]

This report is important news. Some comments here may be redundant to ones already posted.

Here is the full report I used:

biorxiv.org/content/biorxiv...

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Some takeaways I get from it, as I read it:

-Jak2 MPN is likely curable via ridding of only the Jak2 mutant.

-These benefits require near total elimination of Jak2 mutant clones. Implication is allele reduction seen in IFN therapy can be curative by this route but only for those who achieve what is loosely called "undetectable" mutant levels. (is that <1%,... <0.01%...? not clear.)

-Rux is not good enough. I'm not aware of newer Jaki-s having superior Jak2 inhibition by this criteria. If so it points to Jak inhibitor being a nice idea, but we need a "Jak terminator."

-It's limited to Jak2. And, even if they address CALR and MPL by their new test, it doesn't read on triple negative, more evidence MPN is complicated.

-It was on mice, so there is the usual gap in assigning it to humans.

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They used a method that allows Jak2 mutation to be switched on and off. This would be the biggest deal of all, except it's only a lab technique on mice that had Jak2 mutation forced on them via SCT. They don't suggest it is relevant to real Jak2 MPN, only a useful test method using strange things like: (Jak2Rox/Lox/Jak2RL) that allows the v617f version to be turned off. But maybe knowledge here can extend to turning off the real thing?

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-Rux isn't good enough:

<<Loss of Jak2V617F also abrogated erythropoietin-independent erythroid differentiation in vitro, an effect not observed when cells were exposed to the JAK inhibitor ruxolitinib>>

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-This is what eliminated the mutation: <<were administered tamoxifen (TAM) to delete Jak2V617F>> This is a known cancer treatment, but seems it only works here with the special mix of Jak2 the mice were given.

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-More evidence Jak2 is the problem, and it needs to be really gone (what defines gone?):

<<Two of 12 mice demonstrated reemergence/persistence of the MPN phenotype, both of which showed incomplete excision of the Jak2RL allele highlighting the necessity of Jak2V617F in disease maintenance...we conclude that the MPN phenotype requires maintenance of oncogenic signaling through Jak2V617F...Recurrent MPN, as was seen in the non-competitive setting, was observed in 3 of 14 mice across both early- and late- treatment arms and corresponded with residual mutant Jak2V617F expression>>

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Removing the Jak2 mutant also reduced known MPN inflammatories: IFNγ, TGF-β, TNFα were significantly reduced. Might this suggest that inflammation is 2ndary to the main mutational cause, rather than a co-equal in MPN progression?

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More evidence Rux isn't good enough, note "much less":

<<JAK-STAT target gene expression and erythroid pathway gene expression were much less potently inhibited with ruxolitinib than with Jak2V617F deletion...Expression of the gene sets associated with TGF β (p = 0.65)214 and TNFa/NFkB inflammatory signaling pathways were also not significantly altered with ruxolitinib treatment, in contrast to Jak2V617F deletion...These data indicate that current JAK inhibitors do not sufficiently inhibit mutant JAK2 signaling and that more potent target inhibition offers the potential for greater therapeutic efficacy>>

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-They found acquiring TET2 before Jak2 did not reduce the benefit of eliminating Jak2, ie TET2 is not a big problem if Jak2-617 goes away:

<<..suggest a unique dependency on oncogenic Jak2V617F that renders double-mutant cells (Jak2+TET2 in this case) susceptible to eradication....resulted in normalization of hematologic parameters and reductions in peripheral blood mutant cell fraction of double-mutant cells to a similar extent observed with Jak2V617F deletion in single-mutant Jak2RL transplanted mice>>

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Potentially curative:

JAK2V617F mutant-selective inhibition represents a potential curative strategy for the treatment of MPN patients

[Manouche in reply to EPguy]

According to the author : These studies suggest that the most pressing need for MPN patients is better JAK2 inhibitors, whether they more potently target mutant + wt JAK2 or can target JAK2V617F specifically… The problem is the drug, not the target. »

[EPguy in reply to Manouche]

That is consistent with the result. It seems as I noted, we need a Jak Terminator, since even residual mutant allele makes trouble in this report. They didn't provide a definition of "residual", maybe it's in the supplementary data. Under this value would be the goal for improved drugs.

We know that IFN already is superior on avg over Rux for AB reductions via enabling targeting of WT+allele, but with target preference for allele. But I think IFN still leaves "residual" by their definition.