RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia

Journal article

Breast cancer is the second leading cause of cancer death among women in the United States. Due to the various advancements in treatment, the five-year survival rate is greater than 90% among women with non-metastatic breast cancer. However, among patients with metastatic breast cancer, the five-year survival rate quickly drops to 22%. Recognizing early signs of metastasis is essential for targeting cancer before it disseminates. The epithelial-to-mesenchymal transition (EMT) is hypothesized to be a vital process for large-scale cell movement by disrupting cell-cell adhesion, allowing metastatic breast cancer cells to become more migratory. The progression of breast cancer EMT involves multiple genetic and epigenetic events, including the dysregulation of specific tumor suppressor genes such as RUNX1. RUNX1 is a transcription factor that regulates the differentiation of hematopoietic stem cells into mature blood cells and has been recognized as a tumor suppressor in breast cancer. Studies in the Stein laboratory indicated that RUNX1 reduces tumor growth in breast cancer, prevents breast cancer EMT and suppresses stem-like properties in premalignant breast cancer. In this study, the RUNX1 protein was inducibly degraded to determine whether it can lead to breast cancer EMT by regulating the expression of target genes. This EMT progression was monitored by examining cell morphology, RNA expression, and protein expression of target genes in the MCF10A (normal-like) breast cells upon degradation of RUNX1. Loss of RUNX1 protein leads to increased EMT by increasing mesenchymal markers and properties. A potential interplay between RUNX1 and RUNX2 was observed, where the loss of RUNX1 protein results in increased RUNX2 and MANCR; and a decrease in miR15/16 and WWOX. Due to the known role of RUNX1 in the TGFβ pathway and the role of TGFβ in EMT, it is predicted that this regulation is associated with the TGFβ signaling pathway. These findings provide novel insights into the regulation of breast cancer and enhance capabilities for selectively targeting cancer cells before metastasis.PharmacologyMaster of Science (MS

Authors: Matthijssens, F; Sharma, ND; Nysus, M; Nickl, CK; Kang, H

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Society for Clinical Investigation
• Journal: The Journal of Clinical Investigation
• Volume: 131
• Issue: 6
• Pages: 141566
• Publication date: 2021-02-08
• DOI: 10.1172/jci141566
• EISSN: 1558-8238
• ISSN: 0021-9738
• Language: English
• Keywords: Cell biology; Leukemia; RUNX2; Cancer research; Biology; Transcription factor; Immunology; Biochemistry