Science & Medicine

Meet Your Mutations


The naming of cats is a difficult matter

Not just one of your holiday games

At first you may think I am mad as a hatter

When I tell you a cat must have three different names

Just substitute “Mutations” for “Cats” in those opening lines from T.S. Eliot’s Old Possum’s Book of Practical Cats and you have the theme for our Little Almanac of MPN Mutations.

Many of us know our JAK2 status. Positive or negative. And that, indeed, is one name for the mutation that is the primary driver of the majority of MPNs.  But it’s dangerous to omit its other two names: The Janus Kinase and JAK2v617f.

The first Name is shorthand for the gene that produces the protein that does the work. The second name describes the kind of protein produced – in this case an enzyme, a molecule that precipitates an action. The third name is the specific mutation that characterizes this gene in an MPN setting: the substitution of Valine for PHenylanaline in position 617.

So what? It is truly life threatening to consider our JAK2 status the beginning and end of our MPNs. The genetic, environmental and epigenetic factors that led to the V617F mutation that locked the floodgates of blood production on OPEN are part of the MPN pathology.  Blocking – inhibiting the effects of that mutation – may help resolve some short term issues (while creating other longer term health problems) but will have little effect on the underlying disease.

The genomic instability involved in producing a JAK2 positive condition will often involve multiple other downstream mutations, some relatively harmless, some requiring attention. The attention and millions of dollars invested in JAK2 inhibition by Incyte and its luckless competitors has lulled us into the sense that we’re OK once the drug has kicked in, our spleens reduce, appetites increase and we feel better.

Feeling good can be a lethal state. The combination of intense marketing, corrupt medical practices, and the sanctioning of clinical trials without integrity or validity have turned our attention away from the other mutations bred out of our unstable genomic state.  There are dangers of thrombosis and hemorrage from RBC overload, hematocrit out of control, and JAK inhibitors can usually  control some of that for a time.  But we also need to pay attention to the platelet levels in our CBCS – and what that says about our megakaryocytes and their role in spawning inflammatory cytokines that ultimately produce myelofibrosis or acute myeloid leukemia. And to the emerging mutations that drive those diseases.

The Little Almanac of MPN Mutations, with its naming, description and expert comments from scientists on 15 of the most common MPN mutations is designed to help raise our awareness of the nature of mutations driving and expanding our myeloproliferative neoplasms. T

The nature of mutations, genes and DNA Plus the full listing of those 15 mutations are in the MPN Quarterly Journal. You can access the story here.

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