At first glance it’s strange that myeloproliferative neoplasms that arrive via cellular mutation and are driven by one of more mutations do not include overall mutational status in their diagnostic, clinically validated scales.
It is not clear cut whether or not some mutations simply correlate with a phenotypic state or appear as a consequence of an MPN or are causative inmthemselves.. Take JAK2, the first mutation to emerge with unquestioned credentials as an MPN causation mutation.
Simply injecting lab mice with the JAK2 mutation is sufficient to generate an MPN. And while >95% of PV patients are positive for the JAK V617F mutation, it’s possible to be positive for the mutation – as a reportedly up to 60 % of healthy adults are – without a trace of an MPN.
And ruxolitinib, designed to inhibit the activity of this mutant clone in myelofibrosis is effective over some period of time. The drug however is equally effective in MPN patients who don’t have the mutation at all!
Mutations arise in the heat of cellular reproduction, via errors in transcription, frame shift, deletions. Transpositions. Most mutations are harmless, some few are helpful, and others are deadly. They are affected not only by innate genetically driving forces but by epigenetics, the environment in which the mitotic division takes place, by diet, mood, gut microbes, etc.
As a result, the findings that might show up in the gene panel results MPN patients acquire at considerable cost can be misleading. The dreaded ASLX-1 mutation may be of no significance to your prognosis and the clean bill of health indicated by the absence of the three major driving mutations may mean you’re in for a rough ride.
So why add mutational status to the Myelofibrosis Risk Assessment Tool (M/RAT) that already includes two tested and validated scales< DIPSS and DIPPS+ ?
For all that is unknown about the role mutations play in creating and expanding MPNs, much is now known thanks to the very considerable body of work done in the past few years. Most notable is the encyclopedic breadth and statistical analyses of Grinfeld, Nangalia et al’s Classification and Personalized Prognosis in Myeloproliferative Neoplasms, published in the New England Journal Of Medicine in late 2018. Advances in Next Generation Sequencing and expansion of the biomarker database through research and publication, has lent a new hard edged reality to the prognostic significance of mutations.
Here is a brief handful of sources to consult for more detailed information. Each of these publicat9ons has its own rich bibliography.
Ciboddo, Mullaly, AH education book, 2018… Jak2 (and other genes) be nimble with MPN diagnosis….pp 110-115
Grinfeld, Nangala et al., NEJM, Ovtober, 2018,.. Classification and Personalized Prognosis in Myeloproliferative Neoplasms.
Valletta, S et al., Oncotarget, 2015…ASLX1 mutation correction by CRISPR/Cas9 restures gene function…
Tefferi, A et al., Leukemia,2014…CALR and ASXL1 mutaitons-based molecular prognositication in primary myelofibrosis…
Tefferi, A et al., Blood, Nov, 2016, Targeted deep sequencing in polycythemia vera and essential thrombocythyemia.
Patel, A, et al. Clinical Cancer Research, 2016, New strategies in myeloproliferative neoplasms, the evolving genetic and therapeutic landscape.
Schuschlik, F, Karlovics, R. Expert Rev Hematol 2017, Mutations in myeloproliferative neoplasms – their significance and clinical use
JAK2
CALR
ASXL1
TET2
SSF2
MPL
SF3B1
DNMT3A
KMT2A
CBL
IDH2\DLT3
U2AF1
EZH2
TP53
Other