Abstract
Similar signaling pathways could operate in both normal hematopoietic stem and progenitor cells (HSPCs) and leukemia stem cells (LSCs). Thus, targeting LSCs signaling without substantial toxicities to normal HSPCs remains challenging. SALL1, is a member of the transcriptional network that regulates stem cell pluripotency, and lacks significant expression in most adult tissues, including normal bone marrow (NBM). We examined the expression and functional characterization of SALL1 in NBM and in acute myeloid leukemia (AML) using in vitro and in vivo assays. We showed that SALL1 is expressed preferentially in LSCs- enriched CD34+CD38- cell subpopulation but not in NBM. SALL1 inhibition resulted in decreased cellular proliferation and in inferior AML engraftment in NSG mice and it was also associated with upregulation of PTEN and downregulation of m-TOR, β-catenin, and NF-қB expression. These findings suggest that SALL1 inhibition interrupts leukemogenesis. Further studies to validate SALL1 as a potential biomarker for minimal residual disease (MRD) and to determine SALL1’s role in prognostication are ongoing. Additionally, pre-clinical evaluation of SALL1 as a therapeutic target in AML is warranted.
Highlights
Acute myeloid leukemia (AML) is characterized by excessive expansion of myeloblasts in the bone marrow
We identified a SALL1 isoform that is expressed in acute myeloid leukemia (AML), and preferentially in the leukemia stem cells (LSCs) enriched CD34+/CD38subpopulation, but not in normal bone marrow (NBM)
In this study we showed that SALL1 protein is not expressed in NBM And that it is expression pattern in AML is strictly nuclear
Summary
Acute myeloid leukemia (AML) is characterized by excessive expansion of myeloblasts in the bone marrow Regardless of their morphologic subtypes, only a fraction of these cells can recapitulate leukemia generation in sublethally irradiated NOD/SCID mice [1]. LSCs are not successfully targeted or sensitive to current chemotherapy or immunotherapy regimens because they are mostly quiescent, express multidrug resistant genes (MDRs), and are likely less immunogenic than more mature progenitors [8]. Because they share essential cellular pathways with normal HSPCs like Bmi, PTEN and quiescence genes [9, 10]. Because they share essential cellular pathways with normal HSPCs like Bmi, PTEN and quiescence genes [9, 10]. one major challenge in targeting LSCs is identifying pathways that are not required for normal HSPC survival and differentiation to minimize detrimental hematopoietic toxicity
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