Targeting JAK2 Kinase in Lymphoma
These studies in the University of Iowa/Mayo Clinic Lymphoma SPORE are designed to understand the mechanisms of JAK/STAT pathway activation and to study a new JAK2 kinase inhibitor in a clinical trial for relapsed lymphoma.
The overall goal of the Targeting JAK2 Kinase in Lymphoma research project is to identify the molecular mechanisms underlying activation of the JAK/STAT pathway in lymphoma and to learn if inhibitors of this pathway can produce clinical benefit.
The project team has identified several novel missense mutations in JAK2 and STAT3 genes.
The project's preliminary data demonstrate aberrantly activated JAK2 and STAT3 in more than 50 percent of diffuse large B-cell lymphoma samples from patients. In vitro inhibition of JAK2 with the novel JAK2 inhibitor TG101348 (TG) inhibited JAK2 and STAT3 phosphorylation and induced apoptosis in a variety of lymphoma cell lines and patient samples.
This project has four aims.
Aim 1: To characterize the biological significance of novel mutations in the JAK/STAT pathway in lymphoma
The project team is assessing the function of the novel L393V and M206K JAK2/STAT3 missense mutations. Suppressors of cytokine signaling (SOCS1) and protein tyrosine phosphatases (SHP1) are known key negative regulators of the JAK/STAT pathway. The project's preliminary data demonstrate silencing of SHP1 and SOCS1 genes in 33 percent and 86 percent of diffuse large B-cell lymphoma samples.
Aim 2: To delineate the mechanisms of loss of negative regulation of the JAK/STAT pathway in lymphoma
The project team is delineating the mechanisms of silencing and how this regulates JAK/STAT pathway activation. The JAK/STAT signaling pathway is utilized by a number of growth factors and cytokines. The project has identified increases in several JAK/STAT pathway-specific cytokines (IL-2, IL-6, IL-10 and EGF) in serum samples from patients with diffuse large B-cell lymphoma compared to patients without lymphoma. In vitro, the team found that JAK2 and STAT3 are rapidly activated in response to IL-10 in lymphoma cells.
Aim 3: Identify the role of JAK2-specific cytokine-mediated signaling in lymphoma
The project is investigating the role of signaling mediated through their receptors for these interleukins with a focus on IL-10.
Aim 4: Determine the clinical activity of JAK inhibitors in a phase II trial
These agents are in clinical trials at Mayo Clinic for myeloproliferative neoplasms and have been found to be safe with clinical activity. The project team is using a unique trial design to test the hypothesis that preselection will improve the overall response rate. Specifically, the team is stratifying patients based on tumor cell STAT3 activation status: Group A (tumors with activation of JAK/STAT) and Group B (those without activation). Translational studies are using patient serum and tumor samples to investigate the relationship of tumor STAT3 activation, serum cytokines, and other biomarkers with tumor response and clinical outcome.
Co-leaders of this Lymphoma SPORE project are: