calr mutation new information

[Green1988]

nature.com/articles/s41408-...

can someone break this down for me ? I’m confused . Thanks

[hall2]

I can’t make head or tail of it!

[Green1988 in reply to hall2]

I was hoping someone can break it down for me.

[Leveret20]

In a nutshell - they looked at two different types of mutation in CALR, and found a possible mechanism for why one type tends to give faster progression of MPN disease than the other. Implications for treatment are a long way off, but it suggests new lines of research for understanding how CALR mutations cause disease.

***

Their subjects all had a CALR mutation classified as myelofibrosis-type megakaryocyte dysplasia (MTMD)

(I think this means either pre-MF or actual MF).

They studied two different classes of mutation in the CALR gene. The two types of mutation have different effects on spleen size and platelet count.

For the first (Type1), there is a higher rate of progression of MPN disease, but no increase in risk of leukaemia, and no indication of lower survival rates.

Their hypothesis is that this type of CALR mutation may affect the EXPRESSION of other genes important in blood cell production, as well as its direct effect on the CALR function itself.

They looked at one of the genes (CD34/CXCR4) whose expression might be affected by the CALR mutation, and found that the higher the VAF of the CALR, the lower the expression of this gene.

So it is worth further investigation of whether CALR Type 1 mutations are also affecting the expression of other genes in developing blood cells.

**

For the second (Type 2), progression appears slower, VAF is usually lower, and there is no correlation between VAF and the expression of (CD34/CXCR4).

**

**

A quote from their conclusions:

“In summary, we found type 1 CALR mutation is more common in the more severe MTMD category, i.e. overt MF, is associated with lower platelet and higher LDH concentrations, larger spleen size, and earlier development of leukopenia and thrombocytopenia compared with type 2 mutations. Some but not all of these correlations are reported by others [13,14,15]. We also found a strong correlation between type 1 CALR mutation VAF and indicators of disease progression, especially anemia and thrombocytopenia. These data reinforce the impact of type 1 CALR mutation on disease phenotype and trajectory, even though we did not find any influence on survival or progression to leukemia.”

[Green1988 in reply to Leveret20]

Thank you

[hall2 in reply to Leveret20]

Thank you

[socrates_8]

Nice summary Leveret20...

However, I have a Type2 CALR mutation, that is heavily impacted by higher Platelet levels, & LDH in general... I also have an ASXL1+ HRM, along w/ acquired Von Willebrands Syndrome, which complicates my issues further w/ potential TIAs, whenever my Platelets seem to exceed that 1M benchmark. (In other words, each of us is somewhat chemically different in our individual constitutional disorder, in my view... very hard to generalise).

My Dx is Post ET / MF my VAF for CALR was 40%; ASXL1+ 25% & BMB initially Grade2. However, Ruxolitinib returned my slightly enlarged spleen to normal in quick time. Methotrexate (MTX) is used to manage my Platelet levels, when required. Do not enjoy using MTX at all... as several side-effects are heightened; including fatigue & brain fog, hair-thinning & skin sensitivity w/ prolonged use...

As mentioned by the article in question, this was a small sample using mainly mice modelling & as cited by references within the article, there's a conflict in the diversity of variations between observed differences of the two (2) main types of CALR (1 & 2).

However, the article itself helps me realise that suggestions of VAF levels do indeed make some difference to progression, whereas many previous article concerning VAF levels more generally contend that the converse is true...

Hence, the jury is still out, in my view...

Best wishes

Steve

(Sydney)

[Green1988]

Thanks Steve for your reply