Integrated nuclear proteomics and transcriptomics identifies S100A4 as a therapeutic target in acute myeloid leukemia

Abstract

Inappropriate localization of proteins can interfere with normal cellular function and drive tumor development. To understand how this contributes to the development of acute myeloid leukemia (AML), we compared the nuclear proteome and transcriptome of AML blasts with normal human CD34 + cells. Analysis of the proteome identified networks and processes that significantly affected transcription regulation including misexpression of 11 transcription factors with seven proteins not previously implicated in AML. Transcriptome analysis identified changes in 40 transcription factors but none of these were predictive of changes at the protein level. The highest differentially expressed protein in AML nuclei compared with normal CD34 + nuclei (not previously implicated in AML) was S100A4. In an extended cohort, we found that overexpression of nuclear S100A4 was highly prevalent in AML (83%; 20/24 AML patients). Knock down of S100A4 in AML cell lines strongly impacted their survival whilst normal hemopoietic stem progenitor cells were unaffected. These data are the first analysis of the nuclear proteome in AML and have identified changes in transcription factor expression or regulation of transcription that would not have been seen at the mRNA level. These data also suggest that S100A4 is essential for AML survival and could be a therapeutic target in AML.

Absence of S100A4 in the mouse lens induces an aberrant retina-specific differentiation program and cataract

“…Another intriguing question relates to how S100A4 functions in transcriptional repression, given its cytoplasmic localization in lens fibers. Although S100A4 has been found in the nuclei of other cells 3 , 10 , we did not observe the protein in the nuclei of lens fiber cells. Interestingly, S100A10, which belongs to the S100 family of proteins has been demonstrated to regulate breast cancer stem cell specification and pluripotency by regulating H3K27me3 chromatin marks 47 .…”

“…S100A4, used as a prognostic cancer biomarker 3 , has been shown to participate in proliferation, differentiation, cell motility, invasion, and immunity 3 , 4 , 6 – 8 . This protein interacts with several intracellular targets, including actin and non-muscle myosin IIA 9 , and is localized predominantly in the cytosol with some additional distribution to the nucleus 3 , 10 . S100A4 can regulate the signaling activity of various growth factors 11 , 12 , the secretion of matrix metalloproteinases 13 , and the epithelial to mesenchymal transition 3 , 7 .…”

Landscape of Tumor Suppressor Mutations in Acute Myeloid Leukemia

“…With the advent of mass-spectrometry-based methods performed directly on human AML-sorted stem cells, a significant number of leukemia-specific proteins, especially membrane-associated, have been identified. The main objective of this approach has been the identification of novel AML stem cell biomarkers to exploit as immunotherapeutic targets, in order to eradicate the disease [182][183][184][185]. Moreover, patients' proteomic profiles could correlate with the mutational status and thus with the prognosis of AML patients, suggesting that proteogenomic approaches might become the main goal in the near future.…”

Identification of a Prognostic Gene Signature Associated with Microenvironment in Acute Myeloid Leukemia

“…GO analysis revealed that these prognostic DEGs primarily enriched in inflammatory relevant response. Previous study have demonstrated that overexpressed S100A4 was highly prevalent in AML and caused disappointing clinical events [50,51]. Although several genes among these still retained limited evidence regarding the impacts on AML, the correlation between these genes and other tumors or immune response are experiencing a universal investigation.…”