Specific protein 1 (Sp1) is central to regulating transcription factor activity and cell signaling pathways. Sp1 is highly associated with the poor prognosis of various cancers; it is considered a non-oncogene addiction gene. The function of Sp1 is complex and contributes to regulating extensive transcriptional activity, apart from maintaining basal transcription. Sp1 activity and stability are affected by post-translational modifications (PTMs), including phosphorylation, ubiquitination, acetylation, glycosylation, and SUMOylation. These modifications help to determine genetic programs that alter the Sp1 structure in different cells and increase or decrease its transcriptional activity and DNA binding stability in response to pathophysiological stimuli. Investigating the PTMs of Sp1 will contribute to a deeper understanding of the mechanism underlying the cell signaling pathway regulating Sp1 stability and the regulatory mechanism by which Sp1 affects cancer progression. Furthermore, it will facilitate the development of new drug targets and biomarkers, thereby elucidating considerable implications in the prevention and treatment of cancer. 

Role of post-translational modifications of Sp1 in cancer: state of the art

Quiescent self-renewal of leukemia stem cells (LSCs) and resistance to conventional chemotherapy are the main factors leading to relapse of acute myeloid leukemia (AML). Alpha-enolase (ENO1), a key glycolytic enzyme, has been shown to regulate embryonic stem cell differentiation and promote self-renewal and malignant phenotypes in various cancer stem cells. Here, we sought to test whether and how ENO1 influences LSCs renewal and chemoresistance within the context of AML. We analyzed single-cell RNA sequencing data from bone marrow samples of 8 relapsed/refractory AML patients and 4 healthy controls using bioinformatics and machine learning algorithms. In addition, we compared ENO1 expression levels in the AML cohort with those in 37 control subjects and conducted survival analyses to correlate ENO1 expression with clinical outcomes. Furthermore, we performed functional studies involving ENO1 knockdown and inhibition in AML cell line. We used machine learning to model and infer malignant cells in AML, finding more primitive malignant cells in the non-response (NR) group. The differentiation capacity of LSCs and progenitor malignant cells exhibited an inverse correlation with glycolysis levels. Trajectory analysis indicated delayed myeloid cell differentiation in NR group, with high ENO1-expressing LSCs at the initial stages of differentiation being preserved post-treatment. Simultaneously, ENO1 and stemness-related genes were upregulated and co-expressed in malignant cells during early differentiation. ENO1 level in our AML cohort was significantly higher than the controls, with higher levels in NR compared to those in complete remission. Knockdown of ENO1 in AML cell line resulted in the activation of LSCs, promoting cell differentiation and apoptosis, and inhibited proliferation. ENO1 inhibitor can impede the proliferation of AML cells. Furthermore, survival analyses associated higher ENO1 expression with poorer outcome in AML patients. Our findings underscore the critical role of ENO1 as a plausible driver of LSC self-renewal, a potential target for AML target therapy and a biomarker for AML prognosis. 

Single-cell dissection reveals promotive role of ENO1 in leukemia stem cell self-renewal and chemoresistance in acute myeloid leukemia

The Notch pathway is a key cancer driver and is important in tumor progression. Early research suggested that Notch activity was highly dependent on the expression of the intracellular cleaved domain of Notch-1 (NICD). However, recent insights into Notch signaling reveal the presence of Notch pathway signatures, which may vary depending on different cancer types and tumor microenvironments. Herein, we perform a comprehensive investigation of the Notch signaling pathway in adult T-cell leukemia (ATL) primary patient samples. Using gene arrays, we demonstrate that the Notch pathway is constitutively activated in ATL patient samples. Furthermore, the activation of Notch in ATL cells remains elevated irrespective of the presence of activating mutations in Notch itself or its repressor, FBXW7, and that ATL cells are dependent upon Notch-1 expression for proliferation and survival. We demonstrate that ATL cells exhibit the expression of pivotal Notch-related genes, including notch-1, hes1, c-myc, H19, and hes4, thereby defining a critical Notch signature associated with ATL disease. Finally, we demonstrate that lncRNA H19 is highly expressed in ATL patient samples and ATL cells and contributes to Notch signaling activation. Collectively, our results shed further light on the Notch pathway in ATL leukemia and reveal new therapeutic approaches to inhibit Notch activation in ATL cells.

Increased H19/miR-675 Expression in Adult T-Cell Leukemia Is Associated with a Unique Notch Signature Pathway

Construction and experimental validation of a macrophage cell senescence-related gene signature to evaluate the prognosis, immunotherapeutic sensitivity, and chemotherapy response in bladder cancer

The basic helix-loop-helix (bHLH) transcription factor family plays a crucial role in regulating cellular differentiation and development. Inhibitor of DNA binding 1 (ID1), which lacks a DNA-binding motif, functions as a dominant-negative inhibitor of class I and II bHLH factors to antagonize their abilities to bind to DNA and transcriptionally regulate target genes. Given that hematopoiesis is a dynamic and intricate process involving the differentiation of hematopoietic stem and progenitor cells into mature lineage cell types, elucidating the regulatory role of ID1 as a differentiation inhibitor within the hematopoietic system is paramount. Physiologically, ID1 is indispensable for maintaining normal bone marrow function and cell fate determination. However, aberrant ID1 expression, driven by pathogenic mechanisms, such as gene mutations or oncogenic kinases, contributes to the initiation and progression of various blood disorders, particularly leukemia. In this review, we comprehensively summarize the expression patterns of ID1 in hematopoietic and stromal cells within the bone marrow niche, and delve into its modulation of blood lineage commitment and development. While some discrepancies in the literature may arise from differences in experimental models or detection methods, it is evident that precise ID1 regulation is crucial for myeloid-lymphoid fate decisions. Moreover, ID1 overexpression is a causal factor in hematologic malignancies. Encouragingly, significant strides have yielded promising antileukemic effects of ID1 inhibitors, both alone and in combination with targeted therapies against oncogenic signaling pathways. Nevertheless, further efforts are needed to develop innovative and practical strategies that modulate ID1 activity to restore and sustain hematopoietic homeostasis.

ID1 in hematopoiesis and hematologic disorders: novel potentials of a classic differentiation regulator

https://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2022019537/2058424/blood.2022019537.pdf

The cell non-autonomous function of ID1 promotes AML progression via ANGPTL7 from the microenvironment.

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The cell non-autonomous function of ID1 promotes AML progression via ANGPTL7 from the microenvironment.