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Targeting The JAK-STAT Pathway in Malignant and Non-Malignant Cells in Myeloproliferative Neoplasms

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1.8 from 4 votes
Monday, June 17, 2013

Myeloproliferative neoplasms (MPN) are clonal blood disorders characterized 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.

To identify cytokines altered in PMF, we measured serum cytokine levels in MPN mice and in control mice. We 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 normalized aberrant cytokine levels in PMF mice, consistent with the anti-inflammatory effects of ruxolitinib seen in the clinical setting. Importantly, we 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. We demonstrate 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.

Presenter : Ross Levine

Affiliation : Memorial Sloan Kettering Cancer Center, New York, NY USA

Topic: JAK-STAT PATHWAY IN MALIGNANT AND NON-MALIGNANT CELLS CONTRIBUTES TO MPN PATHOGENESIS AND THERAPEUTIC RESPONSE (abstract number S568)

About the EHA Annual Congress

Hematology is a specialty that covers everything to do with blood: its origin in the bone marrow, diseases of blood and their treatments. The latest data on research and developments will be presented. The topics range from stem cell physiology and development, to leukemia, lymphoma, myeloma - diagnosis and treatment; red blood cells -, white blood cells- and platelet disorders; thrombosis and bleeding disorders.

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Source: the EHA Annual Congress
1.75
1.8 from 4 votes
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