the former are later-arising cooperating mutations that are
more involved in disease progression rather than disease
The types of IDH mutations seen in our patients with MPN
(mostly IDH2R140Q and IDH1R132S/C) are distinctly different
than those seen in gliomas (mostly IDH1R132H) and more
similar to those seen in AML, although IDH1R132H was
signiﬁcantly more prevalent in AML. Within the context of
MPN, IDH2R140Q was over represented in chronic-phase ET
and PV, whereas IDH1 mutations were more prevalent in PMF
and blast-phase MPN. More studies are needed to conﬁrm this
apparent trend. Regardless, there is currently no good explana-
tion for the observed diversity in IDH mutation variants among
gliomas and myeloid malignancies and current information
suggests similar biological consequences.
Whether or not
different IDH mutations carry different prognostic relevance in
MPN is currently not known and we did not attempt to address
the particular issue because of our relatively small number of
informative cases. Of note, in a recent study of primary AML
with normal karyotype, different types of IDH mutations
appeared to variably inﬂuence disease-free survival and
complete remission rates.
One particularly interesting observation from the current
study was the signiﬁcant association between mutant IDH and
JAK2 non-46/1 haplotype. The latter phenomenon is further
evidence for the JAK2 mutation speciﬁcity of the previously
described association between the JAK2 46/1 haplotype and
In other words, whereas JAK2 exon 14
mutations have been shown to be associated with JAK2
46/1 haplotype, we did not see the same effect involving MPL
(although others have shown otherwise),
show an association with JAK2 non-46/1 haplotype for IDH
mutations. This latter observation is also consistent with our
previous report on the prognostically detrimental effect of
JAK2 non-46/1 haplotype in PMF;
it is possible that patients
with PMF who are nullizygous for JAK2 46/1 haplotype are
susceptible to additional adverse molecular events, such as IDH
mutations, which might lead to biologically more aggressive
disease. Consistent with this possible scenario, in the current
study, the negative prognostic impact of mutant IDH was
accounted for by the JAK2 46/1 genotype in PMF but not in
blast-phase MPN, in which risk factors other than JAK2 non-46/1
haplotype might have promoted the development of IDH
It is becoming increasingly evident that there are many more
mutations than JAK2 and MPL mutations in BCR–ABL1-negative
MPN including those that involve TET2,
Some of these
mutations might be later-arising and more prevalent in blast-
phase disease. What is currently lacking is a composite
evaluation (that is, concurrent analysis of all relevant mutations),
which includes paired chronic- and blast-phase samples of a
large number of patients with blast-phase MPN. Such an
approach is essential for clarifying the individual pathogenetic
or prognostic contribution of the aforementioned mutations and
their chronological order of appearance. It is very likely that
additional mutations in MPN will be described soon, but
practical relevance in terms of either disease prognostication or
value as drug targets has so far been limited.
Conﬂict of interest
The authors declare no conﬂict of interest.
This study is supported in part by grants from the ‘Myelo-
proliferative Disorders Foundation, Chicago, IL, USA’, ‘The
Henry J. Predolin Foundation for Research in Leukemia, Mayo
Clinic, Rochester, MN, USA’ and ‘Associazione Italiana per la
Ricerca sul Cancro-AIRC Milan, Italy, to AMV’.
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