We recently reported that adhesion molecule CD82 is aberrantly expressed in CD34(+) /CD38(-) leukemia stem cells (LSCs). Here, we report the results of a functional analysis of CD82 in CD34(+) /CD38(-) acute myelogenous leukemia (AML) cells. Short hairpin (sh)RNA-mediated downregulation of CD82 resulted in a decrease in the level of IL-10. In contrast, forced expression of CD82 in CD34(+)/CD38(+) AML cells by transduction with CD82-expressing lentiviral particles resulted in an increase in the levels of IL-10. Notably, exposure of CD34(+)/CD38(-) AML cells to IL-10 stimulated clonogenic growth of these cells. Moreover, downregulation of CD82 by a shRNA dephosphorylated STAT5 in CD34(+)/CD38(-) AML cells. On the other hand, forced expression of CD82 resulted in increase in the levels of p-STAT5 in CD34(+)/CD38(+) AML cells. Chromatin immunoprecipitation (ChIP) assay results indicated that STAT5A binds to the promoter region of the IL-10 gene, while reporter gene assay results indicated stimulation of IL-10 expression at the transcriptional level. These results suggest that CD82 positively regulates the STAT5/IL-10 signaling pathway. Moreover, shRNA-mediated downregulation of CD82 expression in CD34(+)/CD38(-) AML cells dephosphorylated STAT5 in immunodeficient mice. Taken together, our data suggest that the CD82/STAT5/IL-10 signaling pathway is involved in the survival of CD34(+)/CD38(-) AML cells and may thus be a promising therapeutic target for eradication of AML LSCs.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1002/ijc.28348 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
FT538, iPSC-derived NK cells, enhance AML cell killing when combined with chemotherapy.
J Cell Mol Med
January 2025
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Induced pluripotent stem cell (iPSC)-derived natural killer (NK) cells offer an opportunity for a standardized, off-the-shelf treatment with the potential to treat a wider population of acute myeloid leukaemia (AML) patients than the current standard of care. FT538 iPSC-NKs express a high-affinity, noncleavable CD16 to maximize antibody dependent cellular cytotoxicity, a CD38 knockout to improve metabolic fitness, and an IL-15/IL-15 receptor fusion preventing the need for cytokine administration, the main source of adverse effects in NK cell-based therapies. Here, we sought to evaluate the potential of FT538 iPSC-NKs as a therapy for AML through their effect on AML cell lines and primary AML cells.
View Article and Find Full Text PDFA Novel In Vitro Model of the Bone Marrow Microenvironment in Acute Myeloid Leukemia Identifies CD44 and Focal Adhesion Kinase as Therapeutic Targets to Reverse Cell Adhesion-Mediated Drug Resistance.
Cancers (Basel)
January 2025
Department of Clinical and Experimental Medicine, Brighton and Sussex Medical School, Falmer, Brighton BN1 9PX, UK.
Background/objectives: Acute myeloid leukemia (AML) is an aggressive neoplasm. Although most patients respond to induction therapy, they commonly relapse due to recurrent disease in the bone marrow microenvironment (BMME). So, the disruption of the BMME, releasing tumor cells into the peripheral circulation, has therapeutic potential.
View Article and Find Full Text PDFAdvances in DNA/RNA Sequencing and Their Applications in Acute Myeloid Leukemia (AML).
Int J Mol Sci
December 2024
Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
Acute myeloid leukemia (AML) is an aggressive malignancy that poses significant challenges due to high rates of relapse and resistance to treatment, particularly in older populations. While therapeutic advances have been made, survival outcomes remain suboptimal. The evolution of DNA and RNA sequencing technologies, including whole-genome sequencing (WGS), whole-exome sequencing (WES), and RNA sequencing (RNA-Seq), has significantly enhanced our understanding of AML at the molecular level.
View Article and Find Full Text PDFUnlocking the Heterogeneity in Acute Leukaemia: Dissection of Clonal Architecture and Metabolic Properties for Clinical Interventions.
Int J Mol Sci
December 2024
School of Medicine and Surgery, University of Milan-Bicocca, 20126 Milan, Italy.
Genetic studies of haematological cancers have pointed out the heterogeneity of leukaemia in its different subpopulations, with distinct mutations and characteristics, impacting the treatment response. Next-generation sequencing (NGS) and genome-wide analyses, as well as single-cell technologies, have offered unprecedented insights into the clonal heterogeneity within the same tumour. A key component of this heterogeneity that remains unexplored is the intracellular metabolome, a dynamic network that determines cell functions, signalling, epigenome regulation, immunity and inflammation.
View Article and Find Full Text PDFIncreased local DNA methylation disorder in AMLs with DNMT3A-destabilizing variants and its clinical implication.
Nat Commun
January 2025
Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.
The mechanistic link between the complex mutational landscape of de novo methyltransferase DNMT3A and the pathology of acute myeloid leukemia (AML) has not been clearly elucidated so far. Motivated by a recent discovery of the significance of DNMT3A-destabilizing mutations (DNMT3A) in AML, we here investigate the common characteristics of DNMT3A AML methylomes through computational analyses. We present that methylomes of DNMT3A AMLs are considerably different from those of DNMT3A AMLs in that they exhibit increased intratumor DNA methylation heterogeneity in bivalent chromatin domains.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!