Results of a preclinical study showed that ablating the thrombopoietin (TPO) receptor (MPL) in Jak2V617F-positive mice prevented the development of myeloproliferative neoplasms (MPNs). The gene Jak2V617F may not be a single entity, as the results of the study recently published in Blood indicate, and the combination of MPL/J Jak2V617F should be considered as an oncogenic complex – both mutations within which are critical for MPN development.
“The fact that just attenuating MPL expression prevented the development of a Jak2V617Fpositive MPN strongly supports the development of MPL antagonists as a novel therapy to treat MPNs,” study author Ian S. Hitchcock, PhD, of the Department of Biology at the University of York, United Kingdom, told ASH Clinical News. “The success of MPL agonists eltrombopag and romiplostim in treating idiopathic thrombocytopenic purpura further highlights that MPL is a viable target for therapeutic intervention in MPNs.”
According to Dr. Hitchcock, the function of Jak2V617F mutation in MPNs has been studied extensively, but the roles played by the cytokine receptors, such as TPO, which interact with the mutated protein, are still unclear. In this study, Dr. Hitchcock and colleagues sought to better characterize how MPL receptor expression and function affected disease progression in Jak2V617F-positive MPN mouse models.
The researchers found that ablating MPL in Jak2V617F+Mpl-/- mice completely prevented the development of the MPN, supporting the essential role played by MPL in development of Jak2V617F-mediated MPNs.
The Jak2V617F+Mpl-/- mice had reduced thrombocytothemia, neutrophilia, splenomegaly, and neoplastic stem cell pool, compared with Jak2V617F mice. In contrast, loss of TPO alone only mildly affected the disease phenotype.
“Surprisingly, we also found that the level of MPL expression dramatically altered MPN pathology,” Dr. Hitchcock said. “Our Jak2V617F+MPL heterozygous mice, which expressed half the amount of MPL protein, failed to develop an MPN and maintained normal blood counts.”
Commenting on the results of this study, Ruben A. Mesa, MD, FACP, chair of the division of hematology and oncology at Mayo Clinic Cancer Center in Scottsdale, Arizona, noted that the researchers’ ability to aggravate the MPN phenotype with selective partial knockouts of MPL was “very interesting.” “This suggests a very intriguing additional therapeutic angle that may be explored for MPNs,” he added.
If an MPL-inhibitor were tested in these diseases, Dr. Mesa commented, “I wonder whether one would have to use an antibody-based approach as an anti-receptor activity. I think clearly one would need to block MPL only partially – a full blockade of MPL probably would lead to severe thrombocytopenia.”
Overall, Dr. Hitchcock said that he and his colleagues hope the results of this work will ignite the search for MPL antagonists as a novel therapy for MPNs.
- Sangkhae V, Etheridge SL, Kaushansky K, Hitchcock IS. The thrombopoietin receptor, MPL, is critical for development of a Jak2V617F-induced myeloproliferative neoplasm. Blood. 2014 October 22. [Epub ahead of print]