SH2B3 encodes the lymphocyte adaptor protein (LNK) which attenuates JAK2 activation and negatively regulates the signaling of the thrombopoietin receptor (MPL) and the erythropoietin receptor. LNK has also shown to bind and regulate mutant signaling molecules found in myeloproliferative neoplasms (MPNs) like MPL-W515L and JAK2-V617F. Several acquired SH2B3 frameshift and missense mutations in the pleckstrin homology domain and NH2-terminal region have been reported in myeloproliferative neoplasms. Somatic mutations of SH2B3 are infrequent in MPN and reported in ~5 to 7% of MPN patients. These mutations can be found in all MPN subtypes and co-exist with other driver genes. In one study, SH2B3 mutations are associated with JAK2, CALR and MPL mutations in 50%, 18% and 13.6% of positive cases. All identified mutations were found throughout the gene, without evidence of a hot spot. SH2B3 mutations may be enriched in blast phase disease with a frequency up to 13% of such cases. Also, approximately 1% of T cell and B cell acute lymphoblastic leukemias have been shown to carry homozygous frameshift or nonsense mutations in SH2B3. Partial deletions of SH2B3 have also been reported in ALL. In addition, the T allele of a nonsynonymous single-nucleotide polymorphism (SNP), rs3184504 (p;W262R, c.784T>C), in exon 2 of the SH2B3 gene has been reported to be more prevalent among JAK2V617F-positive patients than control patients or JAK2 wild type patients. Loss of function mutations in SH2B3 have been shown to lead to increased JAK2/STAT3 signaling and cell proliferation.