JAK1 Somatic Mutation in Myeloproliferative Neoplasm

Aim

For most triple-negative myeloproliferative neoplasms (i.e. wild type for JAK2, CALR and MPL), a molecular diagnosis is not available because access to clinical next generation sequencing (NGS) platforms is limited or expensive. In addition, there are clinical cases which are difficult to fit into the WHO criteria for MPNs, such as MPN-unclassifiable (MPN-U) and atypical CML (aCML). We therefore aimed to use a custom designed, targeted NGS panel to identify other potential driver mutations in a case of triple-negative MPN.

Methods

Routine review of the blood peripheral morphology and bone marrow histology of our patient (a 78-year-old woman presenting with leucocytosis, left shift and thrombocytopenia) was undertaken. A provisional diagnosis of MPN-U or chronic myelomonocytic leukaemia (CMML) was made. Standard mutational testing for BCR-ABL, JAK2, CALR and MPL was performed. A comprehensive panel was designed to discover mutations in most (86 genes) of the JAK-STAT pathway as well as all reported mutations in MPNs up until 2014. We included genes previously reported to be mutated in MPNs, CMML, CNL and related disorders; we also included known positive and negative regulators of the JAK-STAT pathway.

Results

Using this assay, just two single nucleotide variants (SNV) were detected in >200kb of sequenced DNA: (i) a heterozygous SNV in JAK1 leading to a predicted missense mutation, V658I; and (ii) a SNV in ETV6 which is predicted to lead to a conservative amino acid change, G375V. The latter has not been reported in COSMIC and is not in a functionally critical region of the protein, so was considered unlikely to be pathogenic. Transduction of V658I variant of JAK1 has been previously demonstrated to lead to factor independent cell growth of BaF3 cells, whereas transduction of wild type JAK1 does not, so the former mutation in this case is unquestionably pathogenic. The DNA sequences of all the exons of JAK2, MPL, CALR, CBL, SETBP1, SRSF1 and all the other genes on the panel, including those previously linked with aCML and CMML, were normal.

Conclusions

To our knowledge, JAK1 mutations have never been described in MPNs or CMML. We suggest consideration of JAK1 mutations should be undertaken in cases of MPN-U, aCML or CMML which do not otherwise have a molecular diagnosis. Since these diseases are likely to be molecularly heterogeneous, a broad NGS panel is most likely to yield the responsible driver mutation, and is therefore the preferred diagnostic test. This genetic information could of clinical value since the disease is likely to respond to JAK inhibitors which have a strong binding affinity for JAK1 as well as JAK2, such as ruxolitinib.