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 exvivo 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 invitro. 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 exvivo stem cell expansion.
Bibliographical noteFunding Information:
This work was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences (grant no. UL1 TR000055 ), and National Institutes of Health (grant no. K08 HL087951 ). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
S Milanovich and S Rao have received support from the Midwest Athletes against Childhood Cancer Fund. S Milanovich has received a Hyundai Hope on Wheels Scholar Award (no. 2207871 ). S Rao has received an Institutional Research Grant (no. 86-004 ) from the American Cancer Society and a Hyundai Hope on Wheels Hope Grant, and has also received support from the Children's Hospital of Wisconsin Research Institute .
© 2015 ISEH - International Society for Experimental Hematology.
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