Calreticulin and Jak2 as Chaperones for MPL: Insights Into MPN Pathogenesis
Abstract
Fiscal Year 2014 Peer Reviewed Cancer Research Program Topic Areas: This proposal addresses the myeloproliferative disorders, as well as blood cancers. It is responsive to the following Military Relevance Focus Area: Gaps in cancer prevention, diagnosis, early detection, or treatment that may affect the general population but have a particularly profound impact on military health with a Special Focus on cancers associated with conditions, or circumstances, disproportionately represented within the military beneficiary population. Exposure to radiation, chemical and environmental carcinogens may be contributing factors to these blood diseases. Scientific Objective and Rationale: Most "blood" cancers actually manifest in the bone marrow, where red cells and white cells develop from stem cells. The myeloproliferative diseases we will focus on are Essential Thrombocythemia (ET, too many or abnormal platelets) and Primary Myelofibrosis (PMF, where the bone marrow architecture is abnormal and filled with fibers). These diseases can be slow to progress, which means that they can go undetected for months or years. However, they are life-threatening and debilitating for sufferers of the disease. Improvements in treatment have made a huge difference in the last decade, based upon scientific discoveries that almost 60% of individuals with these blood disorders have mutations in a few specific genes. The major gene mutated is JAK2, which encodes a signaling protein. A smaller group of patients have mutations in the MPL gene, which encodes the thrombopoietin receptor that is "upstream" of the Jak2 protein in the signaling pathway leading to platelet production. Just last year, the field was stunned to learn that a significant fraction of the remaining patients (about 30% of the total) have a mutation in the CALR gene. CALR encodes a "housekeeping" protein called calreticulin, which operates within a cellular compartment called the endoplasmic reticulum to ensure that proteins fold properly. MPL and other receptors start out in this compartment, where they interact with calreticulin and other chaperone proteins. Only after folding properly are they are allowed to exit the compartment and progress to the cell surface. Our proposal seeks to understand how three such different mutations can lead to similar diseases. We hypothesize that there is a strong connection. We will use modern microscopy techniques to discover how mutated calreticulin proteins may alter normal "trafficking" of MPL, as well as change signaling in the progenitor cells that produce platelets. We will use cutting-edge cell imaging technologies, as well as the latest genetic engineering methods to generate live cells expressing fluorescently tagged proteins. This project will be conducted by a multidisciplinary, international team with the expertise to make rapid progress. Applicability of the Research to Patients: For the 50% of ET and PMF patients with JAK2 mutations, new drugs are available that target the enzymatic activity of the Jak2 protein. Clinical trials for this class of drugs have led to encouraging results. However, it is presently unclear if the remaining patients who have MPL or CALR mutations will benefit from these new drugs. Our study will determine if there is a strong link between them, potentially leading to alternative therapeutic targets for patients in specific subgroups and/or drug combination strategies that may improve outcome for all patients. As described in the proposal, this is a basic science project. However, because clinicians are key members of our team, we are prepared to move quickly to translate our research findings into either improved diagnostic tests or target identification. For example, Dr. Hermouet s laboratory developed one of first PCR-based reference assays used commercially worldwide to diagnose JAK2-V617F mutations. It is important to note that our use of patient samples is confidential and
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510176
Entities
People
- Bridget Wilson
Organizations
- United States Army
- University of New Mexico