Background: SH2B3 (Src homology 2 B3), an adaptor protein can suppress activation of the JAK-STAT signaling pathway and the cytokine signaling pathway. Co-existence of SH2B3 mutations with IKZF1 deletion and JAK mutations are involved in oncogenesis in myeloproliferative neoplasms (MPN) and acute lymphoblastic leukemia (ALL).SH2B3 mutations and their clinical significance in adult ALL patients are still not well understood. Methods: 106 patients with newly-diagnosed ALL (79 B-cell and 27 T-cell ALL; 14-77 years old) between June 2008 and June 2016 were studied at Zhongda Hospital Southeast University. The 15 normal bone marrow subjects were enrolled as controls. The study was approved by the Ethics Committee of the institute. The 1-7 exons of SH2B3 were amplified from the genomic DNA extracted from fresh mononuclear cells of the patients by polymerase chain reaction (PCR) and nested PCR. The PCR products were extracted by gel purification and sequenced. Median differences between the cohorts were evaluated using a Mann-Whitney U-test. Frequency differences were analyzed using uni- and multivariate Cox model. Relapse-free survival (RFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared by log-rank test. Results: Two kinds of SH2B3 mutations (c.724C>T, p.P242S; c.724C>T, p.P242S ) were detected in 107 ALL patients. The two SH2B3 SNPs were detected in 20 patients with B-ALL, which represents a detection rate is 25.6% (20/79), and in 4 patients with T-ALL, equating to a detection rate of 14.8% (4/27). There was no statistical difference between the detection rate in B-ALL and T-ALL (P>0.05). Both of the SH2B3 SNPs localize in the PH domain. The c.724C>T, p.P242S (rs78894077) on exon2 (n=23, 18.69%), are only detected in the heterozygous genotype (CT). The % CD13 (+) was lower in patients with the SH2B3 P242S mutation than those without the mutation (20% vs. 47%, P=0.031). Deletion of IKZF1, the Ikaros gene is associated with poor prognosis. IK6, is one of the most common and important types of the gene deletion. In our study, IK6 was detected in 13 of 72 ALL samples with adequate DNA. In these 13 patients, 4 of them co-existed with a SH2B3 P242S mutation. No significant difference of prognosis was observed in the 4 patients compared to those lacking SH2B3P242S mutation. However, in the 59 patients without IK6, there were 13 patients harboring the SH2B3 P242S mutant. The EFS (18 months vs. 5 months, P=0.019, OR=0.471, 95%CI= [0.233-0.950]) and OS (32 months vs. 13 months, P=0.038, OR=0.382, 95%CI= [0.146-1.003]) in these patients were significantly longer than the other 46 patients without a SH2B3 mutation. This data indicates that the SH2B3 P242S mutation may be associated with a better prognosis in patients. The c.784C>T, p.R262W on exon4 is detected in 1 Chinese patient (0.93%). There is also a rs3184504 (c.784T>C) SNP recorded in the database. However, we detected both homozygous (CC) and heterozygous (CT) genotypes on the nucleotide 784 site in this cohort. The CC genotypes was observed in 100% (15/15) of the normal controls and 99.07% of the ALL patients. Only one patient (0.93%) harbored the CT genotype. This data indicates that in the Chinese Han population, the CC genotype is dominant, and it should be the wild type genotype. The wild type for the Chinese Han population for the SH2B3 amino acid residue 262 is arginine "R" not tryptophan "W". The "W" in this site is the SH2B3 SNP (R262W) in the population. The patient with this SNP was a 62 year old male. He had a high WBC count (123*10^9/L), a low PLT count (25*10^9/L), BCR-ABL1 fusion (FISH: BCR-ABL1: 220/300), and also had expression of myeloid markers (CD13: 53.9%)when diagnosed. In addition, this patient had co-existing IL7R mutations (c.197T>C, p.I66T; c.254G>A, p.V138I and c.337C>T, p.H165H ) and an IKZF1 deletion, both of which are important members of the JAK-STAT signaling pathway. The patient relapsed 3 times within one year, and died with central nervous system leukemia. Certainly a bigger ALL cohort is needed to confirm if SH2B3 R262W SNP is related to relapse and poor prognosis. Conclusion: Two novel SH2B3 mutations were identified in a Chinese adult ALL cohort study. Our data showed that the different SH2B3 mutations have distinct clinical features, and the SH2B3 mutations may be used as new molecular markers for clinical risk stratification and even prognosis evaluation following a much bigger cohort validation.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.