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.