Altered erythropoiesis via JAK2 and ASXL1 mutations in myeloproliferative neoplasms.
Exp Hematol
; 132: 104178, 2024 Apr.
Article
em En
| MEDLINE
| ID: mdl-38340948
ABSTRACT
Myeloproliferative neoplasms (MPNs) are driven by hyperactivation of JAK-STAT signaling but can demonstrate skewed hematopoiesis upon acquisition of additional somatic mutations. Here, using primary MPN samples and engineered embryonic stem cells, we demonstrate that mutations in JAK2 induced a significant increase in erythroid colony formation, whereas mutations in additional sex combs-like 1 (ASXL1) led to an erythroid colony defect. RNA-sequencing revealed upregulation of protein arginine methyltransferase 6 (PRMT6) induced by mutant ASXL1. Furthermore, genetic perturbation of PRMT6 exacerbated the MPN disease burden, including leukemic engraftment and splenomegaly, in patient-derived xenograft models, highlighting a novel tumor-suppressive function of PRMT6. However, augmented erythroid potential and bone marrow human CD71+ cells following PRMT6 knockdown were reserved only for primary MPN samples harboring ASXL1 mutations. Last, treatment of CD34+ hematopoietic/stem progenitor cells with the PRMT6 inhibitor EPZ020411 induced expression of genes involved in heme metabolism, hemoglobin, and erythropoiesis. These findings highlight interactions between JAK2 and ASXL1 mutations and a unique erythroid regulatory network in the context of mutant ASXL1.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transtornos Mieloproliferativos
/
Neoplasias
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Exp Hematol
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Macau