S100 Proteins in Acute Myeloid Leukemia

Abstract

The S100 protein family contains 20 functionally expressed members, which are commonly dysregulated in cancer. Their wide range of functions includes cell proliferation, cell differentiation, regulation of transcription factors, inflammation, chemotaxis, and angiogenesis. S100 proteins have in several types of cancer proven to be biomarkers for disease progression and prognosis. Acute myeloid leukemia (AML) is a highly heterogeneous and aggressive disease in which immature myeloblasts replace normal hematopoietic cells in the bone marrow. This review focuses on the S100 protein family members, which commonly are dysregulated in AML, and on the consequences of their dysregulation in the disorder. Like in other cancers, it appears as if S100 proteins are potential biomarkers for leukemogenesis. Furthermore, several S100 members seem to be involved in maintaining the leukemic phenotype. For these reasons, specific S100 proteins might serve as prognostic biomarkers, especially in the patient subset with intermediate/undetermined risk, and as potential targets for patient-adjusted therapy. Because the question of the most suitable candidate S100 biomarkers in AML still is under discussion, because particular AML subgroups lead to specific S100 signatures, and because downstream effects and the significance of co-expression of potential S100 binding partners in AML are not fully elucidated yet, we conclude that a panel of S100 proteins will probably be best suited for prognostic purposes.

Figure 1

Important S100 signaling pathways. Most S100 proteins signal via the RAGE receptor, whereas a small selection also signals via TLR4. The pathways sum up the most important downstream signaling effects of S100A8 and S100A9, the most thoroughly studied S100 proteins. S100A8 can induce autophagy via RAGE, while S100A9 may induce cell differentiation via TLR4/Erk-signaling. Additionally, many S100 members can bind p53; the figure highlights the three proteins that are recognized inhibitors of the tumor suppressor.

Figure 2

High S100 protein expression is associated with increased patient survival. (A) Only patients who received intensive induction therapy were included in the cluster; the mRNA levels were median normalized and log(10) transformed prior to unsupervised clustering using the program JExpress. Patients could be divided into two main subgroups according to low (patients L1-L12) and high (patients H1-H10)/intermediate (patients I1-I6) mRNA expression levels. The upper/low expression subgroup showed especially low (blue color) S100A8/A9 expression, whereas the group below, characterized by high expression, showed especially elevated (red color) levels for S100A12 and S100P. Patients with long-term survival (>2.5 years) are indicated to the right. The S100A4 and A10 values represent the mean value of two probes for these genes. B) Kaplan-Meier (calculated by SPSS version 25) comparison of patients with low S100 protein expression (L1-L12) versus patients with median or high levels, i.e., the two subgroups obtained in the cluster. In this patient cohort, elevated levels of S100 proteins are correlated with prolonged patient survival (log-rank test). Because the plot takes into account all eight differently expressed S100 proteins, the improved patient survival might be due to the impact of a single S100 member, to the whole panel of these eight proteins, or to a group of co-expressed genes, which remain to be identified yet.