TY - JOUR
T1 - Altered erythropoiesis via JAK2 and ASXL1 mutations in myeloproliferative neoplasms
AU - Collins, Taylor B.
AU - Laranjeira, Angelo B.A.
AU - Kong, Tim
AU - Fulbright, Mary C.
AU - Fisher, Daniel A.C.
AU - Sturgeon, Christopher M.
AU - Batista, Luis F.Z.
AU - Oh, Stephen T.
N1 - Publisher Copyright:
© 2024 ISEH - Society for Hematology and Stem Cells
PY - 2024/4
Y1 - 2024/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85186493497&partnerID=8YFLogxK
U2 - 10.1016/j.exphem.2024.104178
DO - 10.1016/j.exphem.2024.104178
M3 - Article
C2 - 38340948
AN - SCOPUS:85186493497
SN - 0301-472X
VL - 132
JO - Experimental Hematology
JF - Experimental Hematology
M1 - 104178
ER -