Inflammation Makes for a Logical Therapeutic Target in MPNs
Angela G. Fleischman, MD, The Fleischman Lab, University of California, Irvine, is working on a project titled, “Inflammation as a Driver of Clonal Expansion in Myeloproflierative Neoplasm.”
The study examines inflammation’s role in the pathogenesis of myeloproliferative neoplasm (MPN). JAK2V617F mutated hematopoietic stem and progenitor cells are resistant to inflammation, and this gives the neoplastic clone a selective advantage allowing for its clonal expansion. Because inflammation plays a central role in MPN, it is a logical therapeutic target.
Oncology Learning Network spoke with Dr. Fleischman about the mutated cells and inflammation’s role on MPN.
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Why is the JAK2 mutation of particular interest in the continued understanding of MPN?
JAK2V617F is the most common mutation in MPNs and is sufficient to induce MPNs in experimental animal models. Therefore, understanding how the JAK2V617F mutation affects blood cell development and drives inflammation will lead to novel therapeutic targets for MPNs. The JAK inhibitor ruxolitinib (Jakafi, Incyte) is currently FDA approved and other JAK inhibitors are in various stages of clinical trials.
JAK inhibitors do not significantly reduce the percentage of mutant cells in patients with MPNs, which suggests that they may work through other mechanisms than direct killing of JAK2V617F mutated cells. Other therapeutic agents such as givinostat (HIDAC inhibitor), LCL-161 (inducer of apoptosis), alisertib (Aurora kinase inhibitor), and idasanutlin (MDM2 inhibitor) are being evaluated in MPNs.
How do JAK2-mutated cells react to inflammation in comparison to normal blood producing cells?
We have found that MPN patient monocytes have defective negative regulation of Toll-like receptor signaling that leads to persistent tumor necrosis factor (TNF) production. This is due to their inability to respond to IL-10 which normally serves to dampen TNF production. This excessive TNF production is a feature of both JAK2V617F mutated and non-mutated monocytes from patients with MPNs, which indicates that it is not a direct cell intrinsic consequence of the JAK2V617F mutation. This highlights that both the mutant and normal cells from patients with MPNs must be targeted to reduce inflammation.
How may inflammation play a role in accelerating progression of MPN, specifically to leukemic transformation?
Chronic inflammation harms hematopoietic (blood) stem cells, leading to stem cell exhaustion. We have found that JAK2V617F mutated hematopoietic progenitors are resistant to the negative effects of inflammation. Therefore, inflammation creates an environment that selects for the expansion of JAK2V617F mutant cells.
What are the keys to suppressing inflammation in in MPNs?
JAK inhibitors are strong anti-inflammatory agents and thus are used in autoimmune diseases as well as MPNs. We are working to determine whether lifestyle alterations such as diet can be utilized to reduce inflammation in early stage MPNs.
We have found that a Mediterranean diet successfully reduces inflammatory cytokines in cardiovascular disease studies. We will soon open a prospective Mediterranean diet intervention in patients with MPNs to establish the feasibility of this diet in the MPN population.
