Targeting dual oncogenic machineries driven by TAL1 and PI3K-AKT pathways in T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of thymic T-cell precursors. Overexpression of oncogenic transcription factor TAL1 is observed in 40-60% of human T-ALL cases, frequently together with activation of the NOTCH1 and PI3K-AKT pathways. In this study, we performed chemical screening to identify small molecules that can inhibit the enhancer activity driven by TAL1 using the GIMAP enhancer reporter system. Among approximately 3,000 compounds, PIK- 75, a known inhibitor of PI3K and CDK, was found to strongly inhibit the enhancer activity. Mechanistic analysis demonstrated that PIK-75 blocks transcriptional activity, which primarily affects TAL1 target genes as well as AKT activity. TAL1-positive, AKT-activated T-ALL cells were very sensitive to PIK-75, as evidenced by growth inhibition and apoptosis induction, while T-ALL cells that exhibited activation of the JAK-STAT pathway were insensitive to this drug. Together, our study demonstrates a strategy targeting two types of core machineries mediated by oncogenic transcription factors and signaling pathways in T-ALL

IRF4 as an Oncogenic Master Transcription Factor

IRF4 is a transcription factor in the interferon regulatory factor (IRF) family. Since the discovery of this gene, various research fields including immunology and oncology have highlighted the unique characteristics and the importance of IRF4 in several biological processes that distinguish it from other IRF family members. In normal lymphocyte development and immunity, IRF4 mediates critical immune responses via interactions with upstream signaling pathways, such as the T-cell receptor and B-cell receptor pathways, as well as their binding partners, which are uniquely expressed in each cell type. On the other hand, IRF4 acts as an oncogene in various mature lymphoid neoplasms when abnormally expressed. IRF4 induces several oncogenes, such as MYC, as well as genes that characterize each cell type by utilizing its ability as a master regulator of immunity. IRF4 and its upstream factor NF-κB form a transcriptional regulatory circuit, including feedback and feedforward loops, to maintain the oncogenic transcriptional program in malignant lymphoid cells. In this review article, we provide an overview of the molecular functions of IRF4 in mature lymphoid neoplasms and highlight its upstream and downstream pathways, as well as the regulatory circuits mediated by IRF4

Downregulation of tumor-suppressor gene LHX6 in cancer: a systematic review

Introduction. LIM Homeobox 6 (LHX6) encodes a LIM homeodomain transcription factor, contributes to tissue development and morphogenesis, and is mostly expressed in medial ganglionic eminence and odontogenic mesenchyme. However, it has been reported to play a role in cancer progression. This narrative review summarizes literatures that emphasize the molecular regulation of LHX6 in tumorigenesis

IRF4 drives clonal evolution and lineage choice in a zebrafish model of T-cell lymphoma

10.1038/s41467-022-30053-9NATURE COMMUNICATIONS13