Date of Award
Doctor of Philosophy (PhD)
Therapeutics and Cell Signaling
Brian P. Sorrentino, MD
Suzanne J. Baker, PhD Wing H. Leung, MD, PhD Janet F. Partridge, PhD Lawrence M. Pfeffer, PhD
Overexpression of HOXB4 in hematopoietic stem cells (HSCs) leads to increased self-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-Sca1+c-kit+ (LSK) cells from mice transplanted with bone marrow (BM) cells transduced with a MSCV-HOXB4-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 genes involved in myeloid and B cell differentiation. Prdm16, a transcription factor associated with human acute myeloid leukemia (AML), was markedly repressed by HOXB4 but upregulated by HOXA9 and HOXA10, suggesting that Prdm16 downregulation was involved in preventing leukemia in HOXB4 transplanted mice. Functional evidence to support this mechanism was obtained by enforcing co-expression of sPrdm16 and HOXB4, which led to myeloid expansion, and leukemia. Before the onset of leukemia decreased HSC frequency was observed in HOXB4and sPrdm16 co-expressing cells, suggesting sustained expression of Prdm16 abolished HOXB4-mediated HSC expansion. Altogether, these studies define the transcriptional pathways involved in HOXB4 HSC expansion in vivo and identify repression of Prdm16 transcription as a mechanism by which HOXB4 mediates a benign HSC expansion.
Yu, Hui , "Downregulation of Prdm16 Is Critical for HOXB4-mediated Benign HSC Expansion In Vivo" (2014). Theses and Dissertations (ETD). Paper 307. http://dx.doi.org/10.21007/etd.cghs.2014.0367.