Discussion
In this paper, we would like to emphasize the following: (i) the CSF3R
polymorphism rs2275472 in donors with the T/C genotype has a negative
impact on the risk for TRM and LFS of patients post allo-HSCT; however,
the rs3917980G/G or A/G genotype is considered a protective factor for
LFS, and (ii) low platelet recovery identifies patients at greater risk
for a poor prognosis.
The first observation that the two different SNPs of CSF3R in healthy
donors have opposite effects on the clinical outcomes of recipients
after allo-HSCT, which is perhaps not well documented in published
studies. Previous studies have shown that CSF3R polymorphisms caused by
mutation or alternative splicing lead to increased or decreased
signaling cascades in response to G-CSF, leading to abnormal clinical
outcomes [9]. CSF3R is widely distributed in
hematopoietic cells, therefore, we hypothesize that as the donors’
hematopoietic stem cells gradually chimerize in recipients, different
SNPs are likely to mediate signal cascades, eventually leading to
diverse clinical outcomes post allo-HSCT. Our further subgroup analysis
results suggest that patients receiving grafts from healthy donors with
the rs3917980 genotype have higher LFS rates than those receiving grafts
from donors with the rs227542 genotype, suggesting that CSF3R site
screening in healthy donors may be used as an indicator to predict the
outcome of patients. However, more research is needed. No one has
discussed the potential effects of these two SNPs on clinical outcomes
so far. Regarding why the CSF3R SNP site in the intron region can affect
the prognosis of transplantation, we speculated that this effect may be
caused by the intron region affecting mRNA expression by changing the
transcription efficiency, splicing or maturation of
mRNA[12]. Our next step may focus on verifying
whether SNP site can affect the transcription and protein expression of
the CSF3R gene by interfering with the intron or exon zone.
The second result of our study was that multivariate analysis showed
that poor platelet recovery was a negative predictor of
transplant-related mortality, leukemia-free survival and overall
survival. This has been elucidated in various reports[13,14,15]. The reason for the above results may
be that poor platelet implantation is related to the occurrence and
development of acute and chronic GVHD, which leads to high TRM, low OS
rates and better LFS[16]. A previous study
elucidated that CSF3R mutations in AML patients were associated with
significantly lower platelet counts[17]. In this
study, we found no association between platelet implantation and SNPs of
CSF3R, and further studies are still needed to explore the clinical
characteristics of patients receiving grafts from healthy donors with
different CSF3R SNPs due to the relatively small number of participants
included in this study.
G-CSF is an important regulator cytokine for the development and
function of neutrophils, and most studies have previously proven that
mutations of CSF3R lead to increased or decreased numbers of neutrophils
because of disorder of the CSF3R signaling
cascade[18]. However, regarding the correlation of
CSF3R SNPs with granulocytes, no reports have been found. In this study,
we found no association between CSF3R SNPs and neutrophil recovery.
Further large prospective studies are needed.
In summary, we have reported that two CSF3R polymorphisms in healthy
donors predicted completely opposite results in recipients, indicating
that a comprehensive assessment of donor CSF3R may be valuable in
patients receiving allo-HSCT. Obviously, these data must be validated in
larger patient cohorts, and the pathophysiological functionality of
these polymorphisms should be further elucidated in mechanistic in vivo
and in vitro models.