JAK1 somatic mutation in myeloproliferative neoplasm

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For most triple-negative MPNs a molecular diagnosis is not available because access to clinical next-generation sequencing (NGS) is limited or expensive. We employed a custom designed NGS panel to identify potential driver mutations in a case of triple-negative MPN. Review of the blood morphology and bone marrow histology of our patient (78-year-old woman presenting with leucocytosis, left shift and thrombocytopenia) was undertaken. A provisional diagnosis of MPN-U was made. Testing for BCR-ABL, JAK2, CALR and MPL mutations was negative. A comprehensive NGS panel was therefore employed to search for a responsible driver mutation. Two single nucleotide variants (SNVs) were detected in >200 kb of sequenced DNA, including a heterozygous SNV in JAK1 leading to a predicted missense mutation, V658I. The V658 amino acid in JAK1 is equivalent to V617 in JAK2, and transduction of JAK1-V658I leads to factor independent cell growth of BaF3 cells, so it is likely pathogenic. To our knowledge, JAK1 mutations have not been described in MPNs. We suggest consideration of JAK1 mutations in cases of MPN-U, aCML or CMML which do not have a molecular diagnosis. This is of clinical value since the disease is likely to respond to JAK inhibitors which have affinity for JAK1, such as ruxolitinib.