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Approximately 50% of children with acute myeloid leukaemia ( AML) relapse, despite aggressive chemotherapy. The bone marrow stromal environment protects leukaemia cells from chemotherapy (i.e., stroma-induced chemoresistance), eventually leading to recurrence. Our goal is to delineate the mechanisms underlying stroma-mediated chemoresistance in AML. We used two human bone marrow stromal cell lines, HS-5 and HS-27A, which are equally effective in protecting AML cells from chemotherapy-induced apoptosis in AML-stromal co-cultures. We found that CYR61 was highly expressed by stromal cells, and was upregulated in AML cells by both stromal cell lines. CYR61 is a secreted matricellular protein and is associated with cell-intrinsic chemoresistance in other malignancies. Here, we show that blocking stromal CYR61 activity, by neutralization or RNAi, increased mitoxantrone-induced apoptosis in AML cells in AML-stromal co-cultures, providing functional evidence for its role in stroma-mediated chemoresistance. Further, we found that spleen tyrosine kinase ( SYK) mediates CYR61 signalling. Exposure to stroma increased SYK expression and activation in AML cells, and this increase required CYR61. SYK inhibition reduced stroma-dependent mitoxantrone resistance in the presence of CYR61, but not in its absence. Therefore, SYK is downstream of CYR61 and contributes to CYR61-mediated mitoxantrone resistance. The CYR61- SYK pathway represents a potential target for reducing stroma-induced chemoresistance. [ABSTRACT FROM AUTHOR]

Simple Summary: To investigate whether pediatric and adult chronic myeloid leukemia (CML) have unique molecular characteristics, we studied the transcriptomic signature of pediatric and adult CML cells using high-throughput RNA sequencing. We identified differentially expressed genes and pathways unique to pediatric CML cells compared to adult CML cells. The Rho pathway was significantly dysregulated in pediatric CML cells compared to adult CML cells, suggesting the potential importance in the pathogenesis of pediatric CML. Our study is the first to compare transcriptome profiles of CML across different age groups. A better understanding of the biology of CML across different ages may inform future treatment approaches. Children with chronic myeloid leukemia (CML) tend to present with higher white blood counts and larger spleens than adults with CML, suggesting that the biology of pediatric and adult CML may differ. To investigate whether pediatric and adult CML have unique molecular characteristics, we studied the transcriptomic signature of pediatric and adult CML CD34+ cells and healthy pediatric and adult CD34+ control cells. Using high-throughput RNA sequencing, we found 567 genes (207 up- and 360 downregulated) differentially expressed in pediatric CML CD34+ cells compared to pediatric healthy CD34+ cells. Directly comparing pediatric and adult CML CD34+ cells, 398 genes (258 up- and 140 downregulated), including many in the Rho pathway, were differentially expressed in pediatric CML CD34+ cells. Using RT-qPCR to verify differentially expressed genes, VAV2 and ARHGAP27 were significantly upregulated in adult CML CD34+ cells compared to pediatric CML CD34+ cells. NCF1, CYBB, and S100A8 were upregulated in adult CML CD34+ cells but not in pediatric CML CD34+ cells, compared to healthy controls. In contrast, DLC1 was significantly upregulated in pediatric CML CD34+ cells but not in adult CML CD34+ cells, compared to healthy controls. These results demonstrate unique molecular characteristics of pediatric CML, such as dysregulation of the Rho pathway, which may contribute to clinical differences between pediatric and adult patients. [ABSTRACT FROM AUTHOR]

The article presents comment on the study that explores the development of an engineered signal transducer and activator of transcription 3 (STAT3) decoy oligodeoxynucleotide (dODN) that is stable in serum taken by target cells. Details of the improtant role played by STAT3 target genes and its clever system into a viable therapeutic molecule are provided. The findings of the study which showed the potential fo STAT3 in alleviating acute myeloid leukemia (AML) are offered.