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| Item Type: | Article |
|---|---|
| Title: | PBX3 is an important cofactor of HOXA9 in leukemogenesis |
| Creators Name: | Li, Zejuan, Zhang, Zhiyu, Li, Yuanyuan, Arnovitz, Stephen, Chen, Ping, Huang, Hao, Jiang, Xi, Hong, Gia-Ming, Kunjamma, Rejani B., Ren, Haomin, He, Chunjiang, Wang, Chong-Zhi, Elkahloun, Abdel G., Valk, Peter J.M., Döhner, Konstanze, Neilly, Mary Beth, Bullinger, Lars, Delwel, Ruud, Löwenberg, Bob, Liu, Paul P., Morgan, Richard, Rowley, Janet D., Yuan, Chun-Su and Chen, Jianjun |
| Abstract: | Although PBX proteins are known to increase DNA-binding/transcriptional activity of HOX proteins through their direct binding, the functional importance of their interaction in leukemogenesis is unclear. We recently reported that overexpression of a 4-homeobox-gene signature (ie, PBX3/HOXA7/HOXA9/HOXA11) is an independent predictor of poor survival in patients with cytogenetically abnormal acute myeloid leukemia (CA-AML). Here we show that it is PBX3, but not PBX1 or PBX2, that is consistently coexpressed with HOXA9 in various subtypes of CA-AML, particularly MLL-rearranged AML, and thus appears as a potential pathologic cofactor of HOXA9 in CA-AML. We then show that depletion of endogenous Pbx3 expression by shRNA significantly inhibits MLL-fusion–mediated cell transformation, and coexpressed PBX3 exhibits a significantly synergistic effect with HOXA9 in promoting cell transformation in vitro and leukemogenesis in vivo. Furthermore, as a proof of concept, we show that a small peptide, namely HXR9, which was developed to specifically disrupt the interactions between HOX and PBX proteins, can selectively kill leukemic cells with overexpression of HOXA/PBX3 genes. Collectively, our data suggest that PBX3 is a critical cofactor of HOXA9 in leukemogenesis, and targeting their interaction is a feasible strategy to treat presently therapy resistant CA-AML (eg, MLL-rearranged leukemia) in which HOXA/PBX3 genes are overexpressed. |
| Keywords: | Acute Myeloid Leukemia, Bone Marrow Cells, Bone Marrow Transplantation, DNA-Binding Proteins, Gene Rearrangement, HEK293 Cells, Histone-Lysine N-Methyltransferase, Homeodomain Proteins, Inbred C57BL Mice, Intercellular Signaling Peptides and Proteins, Leukemic Gene Expression Regulation, Mutant Strains Mice, Myeloid-Lymphoid Leukemia Protein, Peptides, Pre-B-Cell Leukemia Transcription Factor 1, Proto-Oncogene Proteins, Small Interfering RNA, Transcription Factors, Transformed Cell Line, Animals, Mice, Rats |
| Source: | Blood |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Volume: | 121 |
| Number: | 8 |
| Page Range: | 1422-31 |
| Date: | 21 February 2013 |
| Additional Information: | Copyright © 2013 by The American Society of Hematology |
| Official Publication: | https://doi.org/10.1182/blood-2012-07-442004 |
| External Fulltext: | View full text on external repository or document server |
| PubMed: | View item in PubMed |
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