Role of SALL4 in hematopoiesis.
ABSTRACT Stem cell gene SALL4 has been well characterized for its essential role in developmental events as well as embryonic stem cell pluripotency maintenance. Several current reports now shed new light on its functions in regulating hematopoietic cell self-renewal and differentiation. In this review we attempt to summarize SALL4 roles for normal hematopoiesis, and how the knowledge obtained can be used to develop advanced cell therapies.
SALL4 may act as a critical controller to regulate the fate of hematopoietic cells. In normal bone marrow, SALL4 is selectively expressed in primitive hematopoietic precursors and rapidly downregulated following differentiation. Of particular interest, SALL4 isoforms are able to stimulate large scale ex-vivo expansion of hematopoietic stem/progenitor cells (HSCs/HPCs). The SALL4 expanded HSCs/HPCs retain multilineage repopulation and long-term engraftment activities, which are clinically meaningful. The stem cell self-renewal mediated by SALL4 is linked to epigenetic machinery.
The emerging knowledge about how SALL4 regulates HSC behavior may be used in the near future to develop advanced cell therapies, for example, through large-scale stem cell expansion ex vivo.
- SourceAvailable from: PubMed Central[show abstract] [hide abstract]
ABSTRACT: Sall4 is a key factor for the maintenance of pluripotency and self-renewal of embryonic stem cells (ESCs). Our previous studies have shown that Sall4 is a robust stimulator for human hematopoietic stem and progenitor cell (HSC/HPC) expansion. The purpose of the current study is to further evaluate how Sall4 may affect HSC/HPC activities in a murine system. Lentiviral vectors expressing Sall4A or Sall4B isoform were used to transduce mouse bone marrow Lin-/Sca1+/c-Kit+ (LSK) cells and HSC/HPC self-renewal and differentiation were evaluated. Forced expression of Sall4 isoforms led to sustained ex vivo proliferation of LSK cells. In addition, Sall4 expanded HSC/HPCs exhibited increased in vivo repopulating abilities after bone marrow transplantation. These activities were associated with dramatic upregulation of multiple HSC/HPC regulatory genes including HoxB4, Notch1, Bmi1, Runx1, Meis1 and Nf-ya. Consistently, downregulation of endogenous Sall4 expression led to reduced LSK cell proliferation and accelerated cell differentiation. Moreover, in myeloid progenitor cells (32D), overexpression of Sall4 isoforms inhibited granulocytic differentiation and permitted expansion of undifferentiated cells with defined cytokines, consistent with the known functions of Sall4 in the ES cell system. Sall4 is a potent regulator for HSC/HPC self-renewal, likely by increasing self-renewal activity and inhibiting differentiation. Our work provides further support that Sall4 manipulation may be a new model for expanding clinically transplantable stem cells.Journal of Hematology & Oncology 09/2011; 4:38. · 4.46 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: SALL4, a human homolog to Drosophila spalt, is a novel zinc finger transcriptional factor essential for development. We cloned SALL4 and its isoforms (SALL4A and SALL4B). Through immunohistochemistry and real-time reverse-transcription-polymerase chain reaction (RT-PCR), we demonstrated that SALL4 was constitutively expressed in human primary acute myeloid leukemia (AML, n = 81), and directly tested the leukemogenic potential of constitutive expression of SALL4 in a murine model. SALL4B transgenic mice developed myelodysplastic syndrome (MDS)-like features and subsequently AML that was transplantable. Increased apoptosis associated with dysmyelopoiesis was evident in transgenic mouse marrow and colony-formation (CFU) assays. Both isoforms could bind to beta-catenin and synergistically enhanced the Wnt/beta-catenin signaling pathway. Our data suggest that the constitutive expression of SALL4 causes MDS/AML, most likely through the Wnt/beta-catenin pathway. Our murine model provides a useful platform to study human MDS/AML transformation, as well as the Wnt/beta-catenin pathway's role in the pathogenesis of leukemia stem cells.Blood 11/2006; 108(8):2726-35. · 9.06 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The Drosophila tracheal system arises from clusters of ectodermal cells that invaginate and migrate to originate a network of epithelial tubes. Genetic analyses have identified several genes that are specifically expressed in the tracheal cells and are required for tracheal development. Among them, trachealess (trh) is able to induce ectopic tracheal pits and therefore it has been suggested that it would act as an inducer of tracheal cell fates; however, this capacity appears to be spatially restricted. Here we analyze the expression of the tracheal specific genes in the early steps of tracheal development and their cross-interactions. We find that there is a set of primary genes including trh and ventral veinless (vvl) whose expression does not depend on any other tracheal gene and a set of downstream genes whose expression requires different combinations of the primary genes. We also find that the combined expression of primary genes is sufficient to induce some downstream genes but not others. These results indicate that there is not a single master gene responsible for the appropriate expression of the tracheal genes and support a model where tracheal cell fates are induced by the co-operation of several factors rather than by the activity of a single tracheal inducer.Mechanisms of Development 04/2000; 91(1-2):271-8. · 2.38 Impact Factor