Similar to the results obtained by other groups, patients with PMF harboring
ASXL1,
EZH2, and/or
SRSF2 mutations exhibited significantly shorter 5-year overall survival, and these gene mutations are also the poor prognostic factors of PMF that were demonstrated in the Japanese cohort
[37][16]. Furthermore, regarding ET and PV, the frequencies of
ASXL1 and
EZH2 mutations increase as the diseases progresses from ET or PV to prefibrotic PMF and overt PMF, whereas the frequencies of
DNMT3A and
TET2 mutations are unrelated to disease type. This implies that
ASXL1 and
EZH2 mutations are related to disease progression, whereas
DNMT3A and
TET2 mutations may trigger the disease. Logistic regression analysis showed that
ASXL1 mutation-positive ET/PV patients had a high rate of progression to leukemia and myelofibrosis
[38][17].
8. Genetic Background Enhancing the Risk of Developing BCR::ABL1-Negative MPNs
The accumulation of mutations is highly dependent on age, and elderly individuals sometimes develop clonal hematopoiesis because of acquired mutations
[39][40][61,62]. Such individuals are diagnosed with clonal hematopoiesis of intermediate potential (CHIP) or age-related clonal hematopoiesis (ARCH)
[41][42][63,64]. Regarding the development of CHIP/ARCH, it has been experimentally demonstrated using the zebrafish model that mutant clones increase by developing clonal fitness, which is driven by enhanced resistance to inflammatory signals
[43][65]. Notably,
JAK2V617F has been identified with a frequency of approximately 0.1% in an analysis of 49,488 individuals, and 7 patients harboring
JAK2V617F (48 individuals were removed for originally having MPNs) were then considered as CHIP/ARCH in the final cohort. Furthermore, the
JAK2V617F mutant burden in CHIP/ARCH increases by 0.55% per year in the study, implying that the
JAK2V617F-mutated cells acquire a mild growth advantage, and therefore the development of
BCR::ABL1-negative MPNs may progress over time
[44][66]. This implication is supported by another investigation, which clarified that
JAK2V617F mutations occur decades before
BCR::ABL1-negative MPN diagnosis, increase the fitness of HSCs, and induce a megakaryocyte–erythroid differentiation bias
[45][67]. CHIP/ARCH individuals also have an increased risk of developing hematologic malignancies or cardiovascular diseases in patients with additional mutations
[46][68].
Some studies have investigated the impact of genetic background on the risk of developing
BCR::ABL1-negative MPNs. For example, the
JAK2 46/1 haplotype concomitant with
JAK2V617F,
RBBP6,
SH2B3, and
TERT mutations was shown to increase the risk of developing
BCR::ABL1-negative MPNs
[47][48][49][50][51][52][69,70,71,72,73,74]. A GWAS analysis of 888,503 individuals, including 2949 patients with
BCR::ABL1-negative MPNs, identified 17 loci, including
JAK2 and
TERT [53][18]. SNPs located at the identified loci, such as rs17879961 (located at
CHEK2 exon 5) and rs534137 (located at the promoter region of
GFI1B), were considered to induce the instability of HSCs homeostasis and may predispose patients to
BCR::ABL1-negative MPNs.
In addition to SNPs that confer higher susceptibility to develop
BCR::ABL1-negative MPNs, SNPs that affect the phenotype, prognosis, and response to therapies of
BCR::ABL1-negative MPNs have been reported and summarized
[54][75]. Although allelic frequencies are not rare (0.114822 for rs6198, 0.279039 for rs1024611, and 0.444187 for rs2431697 by gnomAD, respectively), a poorer prognosis was observed among patients with PMF harboring both
JAK2V617F and homozygous mutations of rs6198 locating at
NR3C1 than those bearing wild-type
NR3C1 [55][76], rs1024611 at
CCL2 strongly correlated to the
CCL2 expression and the myelofibrosis grade
[56][77], and homozygous rs2431697 at miR-146a was associated with myelofibrosis progression
[57][78].