Unfolding selective pathway dependencies of CALR mutated myeloproliferative neoplasms
Jonas Jutzi
PhD, MDBrigham and Women’s Hospital
Project Term: October 1, 2021 - September 30, 2024
The goal of this study is to selectively eradicate blood cancer cells carrying mutations in a gene called calreticulin. Genes and corresponding proteins required for cancer cell survival but not for the survival of healthy cells will first be targeted in mice, both genetically and by using drugs. Validated drugs will then be tested on patient samples. This study will lay the foundation to the development of tailored treatments for patients with calreticulin-mutated blood cancer.
The focus of this research is to investigate blood cancers called Myeloproliferative Neoplasms (MPN) with a specific focus on essential thrombocythemia and the more aggressive entity called myelofibrosis. Patients with myelofibrosis often have a poor quality of life. Bone marrow transplantation is still the only curing option for MPN patients, which comes with considerable side effects. Therefore, there is an ongoing need for additional targeted approaches that are curative by eradicating malignant MPN cells while sparing healthy cells. My research seeks to uncover such novel treatment options for MPN patients. A protein called calreticulin (CALR) is frequently mutated in patients with MPN. These mutations to the CALR gene result in a defective protein, which leads to an “on” signal in bone marrow stem cells, resulting in constant cell division. Moreover, unmutated CALR acts as a quality check on protein integrity, and our preliminary work shows that the mutated CALR loses that ability. Our preliminary data show that cells carrying a CALR mutation depend on several pathways, particularly those involved in adding sugars to proteins. We aim to validate these findings in a mouse model harboring the mutant CALR protein by depleting crucial factors in this pathway. In parallel, I will perform a drug screen using drugs that are described to target these proteins. I will then test promising compounds in our CALR-mutant MPN mouse model and on patient samples. Another part of my project focuses on the role of CALR in balancing protein synthesis and recycling. Due to an imbalance in protein homeostasis, cells carrying a defective CALR gene activate cellular stress pathways. Usually, this stress involves toxic products that damage the DNA and lead to cell death if exceeding a certain threshold. CALR-mutated cells, however, escape this process by increasing the recycling of defective proteins that can be toxic to cells, thus leading to better survival in these mutated cells under these stress conditions. This makes these CALR-mutant cells vulnerable to the inhibition of this recycling machinery. I will exacerbate cellular stress in CALR-mutated cells using drugs targeting protein recycling. This will cause CALR-defective cells to die while sparing healthy cells. These data will contribute to future research in developing a tailored treatment for patients with a CALR-mutated MPN.