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Blood. 2014 Sep 11;124(11):1737-47. doi: 10.1182/blood-2013-10-534735. Epub 2014 Jul 31.

Downregulation of Prdm16 mRNA is a specific antileukemic mechanism during HOXB4-mediated HSC expansion in vivo.

Author information

1
Experimental Hematology Division, Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN; Integrated Program in Biomedical Sciences, University of Tennessee Health Science Center, Memphis, TN;
2
Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN; and.
3
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.
4
Experimental Hematology Division, Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN;

Abstract

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(+) cells from mice transplanted with bone marrow 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 in genes involved in myeloid and B-cell 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. Functional evidence to support this mechanism was obtained by enforcing coexpression of sPrdm16 and HOXB4, which led to enhanced self-renewal, myeloid expansion, and leukemia. 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 expanding HSCs avoid leukemic transformation.

PMID:
25082879
PMCID:
PMC4162106
DOI:
10.1182/blood-2013-10-534735
[Indexed for MEDLINE]
Free PMC Article
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