MPN Mutant Cell Fitness vs VAF

[EPguy]

A study from I think the Cornell MPN group has a new risk measuring method they found to be a good indication of prognostics for event free survival and treatment response.

Top conclusion is this new measurement method of the mutant cells is much more relevant than allele burden (VAF).

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They developed an unspecified way to rate "MPN fitness - the competitive advantage of mutated hematopoietic stem and progenitor cells (HSPC) over their normal counterparts.."

I understand this to mean a scale (they use F1-F4) measuring how durable the v617f mutated cells are.

"Patients with increased fitness (the bad thing) were more likely to experience an adverse event (33% vs 0%, p=0.047) and were less likely to achieve clinical response (13% versus 75%, p=0.007) than pts with decreased fitness.

Change in WB (whole blood) MAF (VAF) did not correlate with change in fitness (r 2=0.0116) and did not predict events (p=1) nor clinical response"

sciencedirect.com/science/a...

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So fitness of the mutated cells matters more than how many of them there are. The plot here shows the effect of fitness clearly, very large differences.

Maybe this can measure the frustrating variations we see among many of us and inform how well we will respond to treatment as they say.

They plan to do a trial to make this fitness test available clinically. Seems it would not require BMB.

One take is we might have some idea of our F level since events are concentrated in just a couple years: if we make it for two years without an event, odds are higher we are lower on the scale (this is my thought, not theirs)

[Paul123456]

Interesting thanks.

The fitter the mutated cells, then doesn’t this mean that they multiply faster. Hence those of us with a rapidly rising JAK2 are more likely to have ‘fitter’ cells?

[EPguy in reply to Paul123456]

They don't really define this new measure. It's clearly part of survival of the fittest, maybe like a covid virus evolving into Ba.5 for best survival. But unfortunately we don't make antibodies to kill Jak2.

Immune therapy that's our great hope, make artificial antibodies to kill our mutations.

I think faster multiplying is an effect of fitness, implication is they are measuring a source of fitness. But as above, per their plot, events are a proxy for fitness.

[Manouche]

« On any given day, a number of cells in our body are acquiring mutations. “Most of the time, they occur in a cell that doesn’t really much matter,” says Dr. Scandura. “But every now and then, there’s a mutation that occurs in the wrong gene (in a single stem cell).”

For that one founder mutation to become an MPN, “you need time and you need a fitness advantage,” according to Dr. Scandura. “To me, the whole game is why do those stem cells do better than our normal stem cells? Because if you can answer that question . . . and you can prevent that mutated stem cell from taking over, you can prevent the disease. And if you already have the disease? Well, those stem cells, if they can become less comfortable, can become less fit. Then the normal cells might be able to outcompete them.”

It comes down to this, according to Scandura et al. “We need to be understanding and targeting the stem cells, and stem cells don’t exist in a vacuum. They exist in a niche. That niche talks to the stem cell and the stem cell talks to the niche. And the mutant stem cells may be speaking in a language that’s slightly different than normal stem cells and telling the niche to do things that it doesn’t ordinarily do or shouldn’t be doing. So it’s kind of like a corrupting influence.”

mpnresearchfoundation.org/n...

originalText

Stem cell niche

[EPguy in reply to Manouche]

In your link this seems to be a description of the Fitness parameter. But it reads like a basic AB % to me, must be more to it:

"they take the individual cells that are floating around in the blood and separate them. They then analyze how many mutant cells are within each of those populations and turn that back into one composite measure they call MPN fitness"

With this new Fitness parameter "we’re attaching an immediately realizable measure to a predicted outcome and a treatment effect". So rather than wait years to find out how well IFN is working for example, they can use his new measure to know much faster.

[Manouche in reply to EPguy]

Not exactly the same. They analyze how many mutant cells are within each hematopoietic cell type and turn that back into one composite measure called MPN fitness.

[EPguy in reply to Manouche]

A definition of AB that comes up is:

1- "An allele frequency is calculated by dividing the number of times the allele of interest is observed in a population by the total number of copies of all the alleles at that particular genetic locus in the population."

nature.com/scitable/definit...

Fitness as above is :

2- "...analyze how many mutant cells are within each of those (cell) populations"

It seems the difference is AB looks at errors over wild type at a single gene location in a sample of cells while Fitness looks at mutated cells without regard to the gene location over total cells in the sample.

If seeking Jak2 for AB or Fitness it seems 1 and 2 would be the same since Jak2 is always at a same location so the "without regard" would not make a difference.

It's a subtle difference for an amateur, I probably need better genetic background to make sense of it. But I also think they are holding back a more detailed explanation.