ERK1/2 is the signaling pathway primarily activated in myeloid neoplasms carrying t(8;9)/PCM1-JAK2 fusion. A two cases report.

Myelodysplastic/Myeloproliferative neoplasms resulting from an acquired t(8;9)/Pericentriolar material-1 (PCM1)-Janus activated kinase 2 (JAK2) fusion are rare diseases with a widely heterogeneous clinical presentation. Although recent studies showed an activation of the JAK/STAT axis in a PCM1-JAK2-transformed murine fibroblast (Lierman, Blood 2012) or human lymphoma (Ehrentraut, PLOSone 2013) cell lines, the status of JAK/STAT signaling in primary cells from PCM1-JAK2 patients has not been assessed yet. Given this background, we analyzed, in primary cells from two patients presenting with a t(8;9)(p22;24)/ PCM1-JAK2-related myeloid neoplasm, the activation pattern of the main signaling cascades associated to Receptor tyrosine kinases that are most commonly activated in cancer: Mitogen-activated protein (MAP) kinase, JAK/STAT and Phosphatidylinositol 3-kinase (PI3K)/AKT pathway. Clinical presentation of the diseases was different: atypical chronic myeloid leukemia (aCML) and myelofibrosis (MF), respectively. In both cases, FISH analysis documented the t(8;9)(p22;24) and RT-PCR revealed the PCM1-JAK2 fusion transcript. The first patient underwent allogenic bone marrow transplant from HLA-matched sibling donor, while the second was treated with the JAK1/2 inhibitor Ruxolitinib, achieving only partial cytogenetic response. Circulating myeloid progenitors isolated from patients’ peripheral blood (PB) were subjected to western blot analyses with antibodies that separately recognize the total and phosphorylated forms of JAK2, STAT3 and 5, AKT and ERK1/2. PB mononuclear cells from 4 healthy subjects (HS1-4) and K562 cells were utilized as controls. We found reduced levels of phosphorylated STAT3, JAK2, STAT5 and Akt in our patients compared to the four HS. Furthermore, while levels of total ERK were comparable among all conditions, only PCM1-JAK2 cells displayed a robust increase in ERK1/2 phosphorylation. These results demonstrate a peculiar “signaling signature” of these two PCM1-JAK2 fusion cases typified by a selective activation of the ERK pathway. The lack of phosphorylation of both STAT3 and STAT5 suggests that PCM1-JAK2 fusion protein is incapable of activating the JAK/STAT signaling axis. Our molecular data provide a biological rationale for the poor clinical response of the MF patient to Ruxolitinib, and immediately suggest that more efforts need to be done to elucidate molecular mechanisms underlying myeloid neoplasms carrying JAK2 translocations.