In vitro and in vivo effects of JAK2 inhibition in chronic myelomonocytic leukemia.

Abstract

In chronic myelomonocytic leukemia (CMML), colony-forming units granulocyte/macrophage (CFU-GM), which grow in vitro in the absence of exogenous growth factors, arise from the abnormal clone that is responsible for the overproduction of granulomonocytic cells. Previous in vitro findings including ours suggest that divergent molecular aberrations in CMML seem to converge within the GM-CSF signaling pathway. As JAK2 is a sentinel kinase in this pathway, JAK2 inhibition may be an attractive treatment approach in CMML. We investigated the in vitro effects of the specific JAK2 inhibitor TG101209 on the autonomous CFU-GM formation from peripheral blood mononuclear cells of patients with CMML. TG101209 was found to either block or strongly inhibit spontaneous CFU-GM growth in all 10 patients tested. This inhibitory effect was dose dependent and significantly more pronounced as compared to the inhibitory effect on stimulated CFU-GM growth from normal individuals. In a CMML patient with splenomegaly, who was treated with the JAK1/2 inhibitor ruxolitinib off label, we can demonstrate a spleen response and the disappearance of constitutional symptoms which was associated with a decrease in autonomous CFU-GM formation ex vivo. Pharmacological JAK2 inhibition may be an interesting approach to be systematically studied in patients with CMML.

• Authors: Klaus Geissler, Eva Jäger, Agnes Barna, Thamer Sliwa, Paul Knöbl, Ilse Schwarzinger, Heinz Gisslinger, Peter Valent
• Journal: European journal of haematology (Eur J Haematol) Vol. 97 Issue 6 Pg. 562-567 (Dec 2016) ISSN: 1600-0609 [Electronic] England
• PMID: 27157043 (Publication Type: Journal Article)
• Copyright: © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Antineoplastic Agents
• Nitriles
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• ruxolitinib
• Janus Kinase 2

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Proliferation (drug effects)
• Colony-Forming Units Assay
• Dose-Response Relationship, Drug
• Female
• Granulocyte-Macrophage Progenitor Cells (drug effects)
• Humans
• Janus Kinase 2 (antagonists & inhibitors, genetics)
• Leukemia, Myelomonocytic, Chronic (diagnosis, drug therapy, metabolism)
• Male
• Middle Aged
• Mutation
• Nitriles
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Pyrazoles (pharmacology, therapeutic use)
• Pyrimidines
• Tomography, X-Ray Computed