Faculty Collaboration Database

Sall4 overexpression blocks murine hematopoiesis in a dose-dependent manner. Exp Hematol 2015 Jan;43(1):53-64.e1-8

Date

09/24/2014

Pubmed ID

25246269

Pubmed Central ID

PMC4268405

DOI

10.1016/j.exphem.2014.09.004

Scopus ID

2-s2.0-84961288383 (requires institutional sign-in at Scopus site)   16 Citations

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.

Author List

Milanovich S, Peterson J, Allred J, Stelloh C, Rajasekaran K, Fisher J, Duncan SA, Malarkannan S, Rao S

Authors

Subramaniam Malarkannan PhD Professor in the Medicine department at Medical College of Wisconsin
Sridhar Rao MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blood Cells
Bone Marrow
Cell Division
Cell Transformation, Neoplastic
Child
Colony-Forming Units Assay
DNA-Binding Proteins
Fetal Blood
Gene Expression Regulation
Graft Survival
Hematopoiesis
Hematopoietic Stem Cells
Humans
Leukemia, Myeloid, Acute
Mice
Mice, Inbred C57BL
Polycomb Repressive Complex 1
Protein Isoforms
Proto-Oncogene Proteins
Radiation Chimera
Recombinant Fusion Proteins
Transcription Factors