1. Sall4 overexpression blocks murine hematopoiesis in a dose-dependent manner.
- Author
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Milanovich S, Peterson J, Allred J, Stelloh C, Rajasekaran K, Fisher J, Duncan SA, Malarkannan S, and Rao S
- Subjects
- Animals, Blood Cells metabolism, Bone Marrow metabolism, Cell Division, Cell Transformation, Neoplastic genetics, Child, Colony-Forming Units Assay, DNA-Binding Proteins biosynthesis, DNA-Binding Proteins genetics, Fetal Blood cytology, Fetal Blood metabolism, Gene Expression Regulation, Graft Survival, Hematopoietic Stem Cells cytology, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Mice, Mice, Inbred C57BL, Polycomb Repressive Complex 1 biosynthesis, Polycomb Repressive Complex 1 genetics, Protein Isoforms biosynthesis, Protein Isoforms genetics, Protein Isoforms physiology, Proto-Oncogene Proteins biosynthesis, Proto-Oncogene Proteins genetics, Radiation Chimera, Recombinant Fusion Proteins metabolism, Transcription Factors biosynthesis, Transcription Factors genetics, DNA-Binding Proteins physiology, Hematopoiesis genetics, Hematopoietic Stem Cells metabolism, Transcription Factors physiology
- Abstract
Sal-like protein 4 (SALL4) is a transcription factor that exists in two splice isoforms, SALL4a and SALL4b, and regulates transcription in embryonic stem cells, hematopoiesis, and acute myeloid leukemia. Constitutive overexpression of SALL4 in mice induces acute myeloid leukemia. Interestingly, a potential benefit of using SALL4 to facilitate ex vivo hematopoietic stem cell expansion has been proposed. However, distinct roles for how SALL4 contributes to normal versus malignant processes remain undefined. Here we show that SALL4b is the predominant isoform in murine hematopoietic stem cells and progenitors. Overexpression of either SALL4 isoform in hematopoietic stem cells or progenitors impairs hematopoietic colony formation and expansion in vitro. Lineage-negative bone marrow overexpressing SALL4b fails to engraft and reconstitute hematopoiesis when transplanted. We found that both SALL4a and SALL4b overexpression impair hematopoiesis, in part through dose-dependent repression of BMI1. Additionally, we have identified the following potential novel SALL4 target genes in hematopoiesis: ARID5B (SALL4a and SALL4b), EZH2, and KLF2 (SALL4a). Lastly, we found that SALL4 expression is variable in acute myeloid leukemia, ranging from no expression to levels comparable to embryonic stem cells. These results show that SALL4 isoforms contribute to only a subset of acute myeloid leukemia and that overexpression of SALL4 isoforms impairs hematopoiesis through repression of BMI1. Together these data demonstrate the sensitivity of hematopoiesis to appropriately balanced SALL4 expression, highlighting the importance of regulating this dynamic in potential therapeutic applications such as ex vivo stem cell expansion., (Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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