Calreticulin and Jak2 as Chaperones for MPL: Insights into MPN Pathogenesis
Abstract
Calreticulin (CALR) is known to be a major player in the ER quality control of glycosylated proteins. Remarkably, this ubiquitously expressed housekeeping gene is mutated in ~30% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF), 2 of the 8 major myeloproliferative neoplasms (MPNs) as classified by the world health organization. One of the biggest challenges is to understand how Jak2, MPL and CALR mutant proteins can lead to very similar signaling events and phenotypes in these MPNs. Objective/Hypothesis. We hypothesize that ET and PMF phenotypes result from abnormal signaling and aberrant intracellular trafficking events in cells bearing mutations in JAK2, MPL or CALR. In this project, we will acquire a deeper understanding of the interplay between these three gene products. We will compare and contrast intracellular routing for wild-type and mutated proteins, identify their potential intersections, and determine the cellular locations from which signals are propagated. Our work seeks a broader understanding of the pathogenesis of the MPNs and set the stage for development of targeted therapeutic solutions. Our Specific Aims are: Aim 1. To determine the sub-cellular localization of mutant calreticulin, as well as the impact on MPL trafficking and megakaryocyte (MK) ultrastructure. Aim 2. To evaluate mechanisms underlying aberrant signaling in MPNs bearing mutant CALR or MPL. At first, we focused on building a MPN sample bank in order to gain access to primary patients samples carrying JAK2, MPL or CALR mutations. These primary samples were then used to study in depth intra-cellular trafficking and signaling patterns of mutants MPL and CALR.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2017
- Accession Number
- AD1050557
Entities
People
- Bridget Wilson
- Cedric Cleyrat
Organizations
- University of New Mexico