The Expression of SALL4, a Newly Identified Stem Cell Factor, Is Correlated with Chronic Myeloid Leukemia (CML) Disease Progression.

The homeotic gene, SALL4, plays an essential role in the maintenance of embryonic stem cell pluripotent and self-renewal properties by interacting with two other key regulators in ESCs, Nanog and Oct4. Previously, we have demonstrated that SALL4 contributes to acute myeloid leukemia (AML) development in a murine model. Also, Bmi-1, a key regulator in leukemic stem cells (LSCs), is a direct target of SALL4. In this study, through immunohistochemistry and fluorescent activated cell sorting (FACS) analysis, we demonstrated that the expression level of the SALL4 protein correlated well with disease progression in CML. There was no SALL4 positive population detectable in normal whole bone marrow samples or chronic phase CML samples. A distinguish SALL4 positive population was present in accelerated and blastic phases of CML marrows, and overlapped with a subset of CD34+ population. This finding is particular of interesting since committed Granulocyte-Macrophage Progenitors (GMPs) are CD34+/CD38+ cells and have been proposed to be candidates for LSCs in the AML to CML transformation. Decreasing SALL4 expression in a CML cell line (KBM5) down regulated Bmi-1 expression, which resulted in increased caspase-3 activity, induced cell-cycle arrest, and decreased cell proliferation. Furthermore, restoration of Bmi-1 expression rescued apoptosis, increased cell proliferation, and promoted cell-cycle progression. Our data have extended our understanding on the stem cell factor SALL4 in CML transformation and its role in the pathogenesis of CML disease progression. SALL4 can also potentially be used as a novel diagnostic marker for CML transformation.