JANUS KINASE V617F MUTATION DETECTION
IN PATIENTS WITH MYELOFIBROSIS
Nikolova D1,2,*, Yordanov A2, Damyanova V1,2, Radinov A2, Toncheva D1
*Corresponding Author: Dragomira Nikolova, Ph.D., Department of Medical Genetics, Medical Faculty,
Medical University Sofia, 2 Zdrave Street, 1431 Sofia, Bulgaria. Tel: +359888-103-456,
E-mail: dmb@abv.bg
page: 57
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DISCUSSION
Extramedullary hematopoiesis, overstimulated fibroblasts
in abnormal microenvironment, fibrous tissue
deposits in the bone marrow, dysregulation of the normal
production of blood cells, low count of platelets and subsequently
the onset of anemia are characteristic hallmarks
of MF. Generally, it is a rare hematological event, predominantly
diagnosed in elderly individuals aged over 50
years [14-16]. The MF/OMF patients were also rare in our
dataset (20/232 patients confirmed the diagnosis, 8.6%)
and the mean age of the patients was 62 years. The gender
does not affect the occurrence of the disease; there is an
equal distribution men:women (10 vs. 10).
The total survival time of patients with PMF can vary
substantially, as well as the clinical course of the disease
and its progression. It can be diagnosed as primary or
developed as a part of other hematological malignancies
as PV or ET. However, the mechanisms of development
of MF are not completely understood. The JAK2, together
with CALR and MPL mutations, is a common triggering
factor in Philadelphia chromosome-negative MPNs
[17]. The so-called “driver” mutations activate the JAKSTAT
signaling pathway. According to previous reports,
about 85.0% of PMF patients have affected one of the
three genes: JAK2 (60.0-65.0%), MPL (5.0%) or CALR
(20.0-25.0%) [14]. In our study, 20 patients with MF were
analyzed for JAK2 mutation by quantitative PCR; and 12
of them carried the mutant allele (60.0%), which is in accordance
with the data reported by other researchers [4].
The remaining patients (12 individuals) who were accepted
with an initial diagnosis of MF, five were confirmed to
carry ET, six with PV and one remained an unclassified
MPN. This showed that trepanobiopsy is absolutely essential
for the final precision of the diagnosis.
The discovery of the genetic transformation of the
JAK2 gene in the majority of our cases with MF makes
possible their treatment with Jakafi (Ruloxitinib), which is
an approved targeted drug for MF. It is indicated both for
primary and secondary MF, either high- or intermediaterisk
groups. It helps to reduce side effects such as splenomegaly,
abdominal and bone pain. At the same time, it
controls the blood levels of the inflammatory cytokines.
The JAK2 V617F mutation leads to constitutive activation
of JAK/STAT signaling [9]. As the JAK2 mutation is
present in only about 60.0% of patients with MF, it could
not be considered to be the only reason for this pathology.
The triggering event of MF is not yet clarified and
other mutations besides JAK2 have recently been studied
in relation to MF. They include mutations in genes such
as IDH1, IDH2, ASXL1, SRSF2 and EZH2 [2]. In 2019,
Wilms tumor 1 (WT1) expression was investigated in 152
patients with MPNs [18]. The progression of ET and PV
to MF was accompanied by increased levels of WT1 gene
expression. Mutations in a tumor-suppressor gene, TP53,
have also been detected in MPN, especially on older patients
[19]. Some cytogenetic transformations (e.g., additional
chromosome 8, inversion of chromosome 3 and
rearrangements of chromosome 11) have been considered
unfavorable markers for MF [20].
Even though the number of MF patients in our study
are quite few (20 individuals), we could underline the slight
prevalence of males in the mutant allele carriers (seven
men vs. five women), while in the group of non carriers,
females prevailed slightly (three men vs. five women). As
for the age of the patients, the registered difference between
carriers and non carriers of the JAK2 V617F mutation
was 1 year (mean age of carriers:non carriers = 61.4:62.4
years). Whether the male gender and younger age are factors
that contribute to JAK2 mutational status is disputable
and has to be further investigated in a larger cohort of
MF patients. We have not had a case in which the JAK2
mutation occurs simultaneously with other mutations, as
it generally occurs as a single event. However, it could
be associated with a different severity of symptoms from
asymptomatic ET to MF [19]. We could speculate that
other factors rather than genetic could modify the severity of the disease (for example age, gender, comorbidity,
microenvironment in the bone marrow, etc.) [19].
The frequency of MF in our cohort of patients (232
individuals) was estimated to be 8.6% (20 individuals).
The distribution was equal between genders and the mean
age (63.95 years) approaches the mean age given by other
researchers (65 years). The majority of MF patients (60.0%
or 12 individuals) were JAK2 V617F mutation-positive
and thereby treatable by Jakafi (Ruxolitinib). For the other
40.0% of cases (eight individuals), treatment options were
limited. They included erythropoiesis-stimulating agents,
hydroxyurea and immunomodulatory drugs, which have
unconvincing effect in improving patients’ survival.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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