Calreticulin haploinsufficiency augments stem cell activity and is required for onset of myeloproliferative neoplasms
Year: 2020
Type: article
Abstract: Mutations in JAK2, myeloproliferative leukemia virus (MPL), or calreticulin (CALR) occur in hematopoietic stem cells (HSCs) and are detected in more than 80% of patients with myeloproliferative neoplasms (MPNs). They are thought to play a driver role in MPN pathogenesis via autosomal activation of the JAK-STAT signaling cascade. Mutant CALR binds to MPL, activates downstream MPL signaling cascades, and induces essential thrombocythemia in mice. However, embryonic lethality of Calr-deficient mice precludes determination of a role for CALR in hematopoiesis. To clarify the role of CALR in normal hematopoiesis and MPN pathogenesis, we generated hematopoietic cell-specific Calr-deficient mice. CALR deficiency had little effect on the leukocyte count, hemoglobin levels, or platelet count in peripheral blood. However, Calr-deficient mice showed some hematopoietic properties of MPN, including decreased erythropoiesis and increased myeloid progenitor cells in the bone marrow and extramedullary hematopoiesis in the spleen. Transplantation experiments revealed that Calr haploinsufficiency promoted the self-renewal capacity of HSCs. We generated CALRdel52 mutant transgenic mice with Calr haploinsufficiency as a model that mimics human MPN patients and found that Calr haploinsufficiency restored the self-renewal capacity of HSCs damaged by CALR mutations. Only recipient mice transplanted with Lineage-Sca1+c-kit+ cells harboring both CALR mutation and Calr haploinsufficiency developed MPN in competitive conditions, showing that CALR haploinsufficiency was necessary for the onset of CALR-mutated MPNs.
Source: Blood
Authors: Kotaro Shide, Takuro Kameda, Ayako Kamiunten, Yoshinori Ozono, Yuki Tahira, Takako Yokomizo-Nakano, Sho Kubota, Masaya Ono, Kazuhiko Ikeda, Masaaki Sekine, Keiichi Akizuki, Kenichi Nakamura, Tomonori Hidaka, Yoko Kubuki, Hisayoshi Iwakiri, Satoru Hasuike, Kenji Nagata, Goro Sashida, Kazuya Shimoda
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Control of myelofibrosis targeting the amplification mechanism of CALR mutant stem cells and the functional motif of CALR mutant proteins, MPN research focusing on ER stress response and tumor-derived fibrocytes, Mutual role of a driver mutation and abnormality of histone modification in progression of myeloproliferative neoplasms, Regulation of the pathogenesis of myeloproliferative neoplasms with a focus on IFNalpha signaling and the mechanism of renal dysfunction., Myeloproliferative neoplasms research for drug discovery focusing on CALR mutation and fibrocyte, Role of Epigenomic alterations in Myeloproliferative neoplasms
OpenAlex ID: W3013799485