Dr Ross Levine presented results from a study on targeting the JAK-STAT pathway in myeloproliferative neoplasms at the EHA 2013.

Myeloproliferative neoplasms (MPN) are clonal blood disorders characterised by excessive production of mature blood cells.

Patients present with large spleens, systemic symptoms, and high levels of circulating inflammatory cytokines.

The identification of somatic mutations in JAK2, MPL and LNK in the majority of MPN patients led to the development of JAK kinase inhibitors.

JAK1/2 inhibitors improve splenomegaly and systemic symptoms, however the mechanism by which this occurs in patients has not been elucidated.

Serum cytokine levels in MPN mice were measured to identify cytokines altered in PMF and in control mice. Research found that a set of cytokines were markedly elevated in the serum of diseased mice compared to control mice and importantly, many of these same cytokines are elevated in MPN patients.

Further, the JAK1/2 inhibitor ruxolitinib normalised aberrant cytokine levels in PMF mice, consistent with the anti-inflammatory effects of ruxolitinib seen in the clinical setting.

Importantly, it was demonstrated that ruxolitnib must inhibit signaling in both mutant and non-mutant cells, suggesting a novel mechanism of action by which JAK inhibitors demonstrate clinical benefit.

It was demonstrated that signaling cross-talk between mutant and non-mutant populations is an important feature of MPNs. Finally, our studies support the notion that JAK kinase inhibition in malignant and non-malignant cells is required to improve symptoms, reduce disease severity, and to prevent malignant progression in MPN patients.

Source: EHA