Downregulatlon of Prdm16 mRNA Is a specific antlleekemk mechanism during HGXB4-medIated HSC expansion In vivo

摘要

Overexpression of HOXB4 in hematopoietic stem cells (HSCs) leads to increased seif-renewal without causing hematopoietic malignancies in transplanted mice. The molecular basis of HOXB4-mediated benign HSC expansion in vivo is not well understood. To gain further insight into the molecular events underlying HOXB4-mediated HSC expansion, we analyzed gene expression changes at multiple time points in Lin Sea1~+-kit~+ cells from mice transplanted with bone marrow cells transduced with a MSCV-HQXB4-ires-YFP vector. A distinct HOXB4 transcriptional program was reproducibly induced and stabilized by 12 weeks after transplant. Dynamic expression changes were observed in genes critical for HSC self-renewal as well as in genes involved in myeloid and B-celi differentiation. Prdm16, a transcription factor associated with human acute myeloid leukemia, was markedly repressed by HOXB4 but upregulated by HOXA9 and HOXA10, suggesting that Prdm16 downregulation was involved in preventing leukemia in HOXB4 transplanted mice.