The molecular underpinnings of leukemic transformation in myeloproliferative neoplasms (MPN) are not well characterized. We used Whole Exome Sequencing (WES) as a screening tool to gain further insight into the genomic origin of MPN progression to blast phase disease. WES analysis was performed in 6 JAK2V617F(+) MPN patients for which paired samples from chronic and blast phase disease were available. Respective clinical data were incorporated into the evaluation, and variations of interest were validated by conventional Sanger sequencing. Single-nucleotide-polymorphism database (dbSNP) was used to exclude/include established germline aberrations. Using WES filtering for non-synonymous variations as predicted deleterious, we detected a significant number of genetic abnormalities in both chronic and blast phase of MPN; these could be functionally linked to “tumorigenesis” (157 genes), “cancers and tumors” (159 genes) and “hematological neoplasia” (48 genes). In both phases of MPN, we could find mutations in genes already known to be linked with the development and/or transformation of MPN (ie, MPL, TET2, EZH2, IDH1, NRAS, LNK, TP53, WT1). Notably, eight genes were identified exclusively at onset of leukemic transformation and could be classified as potential driver mutations with damaging translational impact; these novel mutations could be grouped into “transcriptional regulators” (CUX2, ORC2, KDM6B, CNOT3, TBL1XR1), “NOTCH-signaling pathway” (NOTCH2NL, NOTCH1) and “tyrosine kinases” (STAP2). Moreover, we also identified several single-nucleotide polymorphisms encoding amino acid substitutions (ie, non-synonymous changes) in receptor as well as cytoplasmatic tyrosine kinase genes. Interestingly, the JAK-family member TYK2 showed the largest number of rare non-synonymous polymorphisms (A165T, V362F, G363S, I684S) leading to missense mutations in 67% (4/6) of the MPN patients; in contrast, none of 30 control samples with other types of cancer showed sequence variances in the TYK2 gene. Deficiency of TYK2 has shown to impair tumor surveillance and increase the susceptibility for neoplasia including AML. The present study demonstrates recurrent germline sequence variants in the non-receptor tyrosine kinase TYK2, and novel functionally-relevant somatic mutations with potential pathogenetic contribution to leukemic transformation in MPN.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.