The V617F JAK2 Mutation Is Uncommon in Cancers and Mutations in STAT5A, STAT5B and the JAK Family Genes Do Not Account for V617F Negative Myeloproliferative Disorders.

The JAK2 V617F mutation is present in 97% patients with polycythemia vera (PV) and approximately 50% of patients with essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). JAK2 is widely expressed and is a critical component of signaling pathways in multiple cell types. It remains unclear to what extent the V617F mutation contributes to the pathogenesis of non-hematological cancers and hematological malignancies other than the classical myeloproliferative disorders.

To determine the frequency with which the V617F mutation occurs in a broad range of human malignancies, we sequenced 486 cell lines derived from over 30 different histological types of solid tumor, together with 132 cell lines derived from hematological malignancies. Only the HEL cell line, which was derived from an erythroleukemia, was positive for the mutation. We then screened a further 211 primary hematological malignancies and found the mutation in 5/90 AML patients, 1/20 myelodysplastic syndrome (MDS) and 1/91 chronic myeloid leukemia (CML) patients. The five V617F positive AML patients were male, significantly older than wild-type AML patients and did not have FLT3-ITD mutation, or the t(8;21), inv(16) or t(15;17) rearrangements. In addition, none of the five patients had a history of a prior overt myeloproliferative disorder (MPD). The V617F positive MDS patient was unusual in that he had trephine features of myelodysplasia with fibrosis, consistent with a myelodysplasia/myeloproliferative overlap syndrome. The V617F-positive CML patient had a twelve-year history of BCR/ABL-negative thrombocytosis prior to presenting with CML.

The molecular basis of the V617F-negative MPDs remains obscure. We therefore screened samples from 24 MPD patients without the V617F allele for alternative JAK2 mutations, and for mutations in other components of the JAK/STAT pathway. All 128 coding exons of JAK1, JAK2, JAK3, TYK2, STAT5A and STAT5B were sequenced in peripheral blood granulocyte DNA from 19 ET and 5 IMF patients that lack the V617F allele. No mutations were detected in these individuals.

Collectively, these data suggest that the JAK2 V617F mutation does not occur in non-haematological cancers, that this mutation is uncommon in myeloid malignancies other than the classic BCR/ABL-negative MPDs, and that the V617F-negative MPDs are likely to reflect mutations in other molecules that modulate the JAK/STAT pathway, or mutations in different signaling pathways.