Upregulation of Tim‐3 is associated with poor prognosis in acute myeloid leukemia

Wu, Zhengwei; Ou, Jiawang; Liu, Nannan; Wang, Zhixiang; Chen, Junjie; Cai, Zihong; Liu, Xiaoli; Yu, Xiao-Hong; Dai, Min; Zhou, Hongsheng

doi:10.1002/cam4.5549

Cited by 8 publications

(8 citation statements)

References 54 publications

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“…A recent study highlighted the potential significance of upregulated Tim-3 as a prognostic marker, indicating an unfavorable prognosis for individuals diagnosed with AML. Moreover, the biological properties of Tim-3 were found to be associated with immune responses and signaling pathways involved in the regulation of LSCs 13 . The identification of hub genes displaying differential expression levels in relation to Tim-3 may offer valuable opportunities to deepen our understanding of prognosis and the role of LSCs within the Tumor Immune Microenvironment (TME) of AML.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, by analyzing somatic mutations, it has been determined that multistep leukemogenesis arises from self-renewing HSCs, highlighting Tim-3 as a potential target for selectively eliminating LSCs while preserving residual HSCs 11 . In a recent investigation involving 302 AML patients, Tim-3 was detected in LSCs at the time of initial diagnosis in 78.5% of cases 12 , 13 . Moreover, Tim-3 serves as an immune checkpoint and plays a critical role in immune responses during AML 14 .…”

Section: Introductionmentioning

confidence: 97%

“…Though a study reveals the expression of Tim-3 may affect prognosis in AML patients 13 . The precise mechanisms through which TIM-3 impacts the prognosis of individuals with AML are currently lacking in comprehensive understanding.…”

Section: Introductionmentioning

confidence: 99%

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Identification and validation of a prognostic risk-scoring model based on the level of TIM-3 expression in acute myeloid leukemia

Huang,

Zheng,

Wang

et al. 2023

Sci Rep

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Acute myeloid leukemia (AML) is characterized by an unfavorable prognosis due to the presence of self-renewing leukemic stem cells (LSCs). The presence of T-cell immunoglobulin mucin-3 (TIM-3) on the surface of LSCs has been observed in various types of human AML, exerting an impact on the prognostic outcome. Exploring the hub genes associated with varying levels of TIM-3 expression offers a valuable approach to enhance our understanding of the underlying mechanisms involving TIM-3 and to identify potential prognostic indicators in AML. Nevertheless, to date, no research studies have reported a prognostic model that relies on the level of TIM-3 expression. In our study, we screen the hub-genes based on different expression level of TIM-3 through WGCNA. The prognostic risk-scoring model was constructed based on hub-genes. The results show the risk prognostic model has extraordinary ability to predict prognosis in both the training and validation sets. The high-risk group present poor prognosis with mutation of NPM1, TP53 (Multiple Hit) and FLT3(multiple hit), while IDH2 (Missense Mutation), MUC16 (Multiple Hit/Missense Mutation) occur mutation in low-risk group presenting favorite prognosis than high-risk group. Leukocyte cell–cell adhesion, regulation of T cell activation and I-κB kinase/NF-κB signaling enriched in high-risk group, involving in HSCs or LSCs anchoring to BM, which implicated in LSCs survival and chemotherapy resistance. B7-H3 (CD276) and CD276 would be the potential immune targets in high-risk group. The risk score model may help in distinguishing immune and molecular characteristics, predicting patient outcomes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Identification and validation of a prognostic risk-scoring model based on the level of TIM-3 expression in acute myeloid leukemia

Huang,

Zheng,

Wang

et al. 2023

Sci Rep

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“…This interaction is known to negatively regulate CD8+ T-cell activation and Th1-type immunity by inducing cell death ( 107 ). TIM-3 appears to be a marker of exhaustion and an increased number of exhausted PD-1 + /TIM-3 + CD8 + T-cells has been associated with disease progression and poorer prognosis in AML ( 108 , 109 ). Preliminary in vivo studies have shown that blockade of TIM-3 prevents engraftment of leukemic stem cells without inhibiting normal stem cell engraftment ( 110 ).…”

Section: Other Targetable Checkpoint Moleculesmentioning

confidence: 99%

Checkpoint inhibition in hematologic malignancies

Tsumura,

Levis,

Tuscano

2023

Front. Oncol.

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Checkpoint inhibitor therapy has emerged as an effective therapeutic strategy for many types of malignancies, especially in solid tumors. Within the last two decades, numerous monoclonal antibody drugs targeting the CTLA-4 and PD-1/PD-L1 checkpoint pathways have seen FDA approval. Within hematologic malignancies, Hodgkin Lymphoma has seen the greatest clinical benefits thus far with more recent data showing efficacy in the front-line setting. As our understanding of checkpoint inhibition expands, using these pathways as a therapeutic target has shown some utility in the treatment of other hematologic malignancies as well, primarily in the relapsed/refractory settings. Checkpoint inhibition also appears to have a role as a synergistic agent to augment clinical responses to other forms of therapy such as hematopoietic stem cell transplant. Moreover, alternative checkpoint molecules that bypass the well-studied CTLA-4 and PD-1/PD-L1 pathways have emerged as exciting new therapeutic targets. Most excitingly is the use of anti-CD47 blockade in the treatment of high risk MDS and TP-53 mutated AML. Overall, there has been tremendous progress in understanding the benefits of checkpoint inhibition in hematologic malignancies, but further studies are needed in all areas to best utilize these agents. This is a review of the most recent developments and progress in Immune Checkpoint Inhibition in Hematologic Malignancies in the last decade.

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“…These cell surface markers have diverse cellular roles which co-ordinate the external stimuli to the internal cellular environment. Inhibitory immune checkpoint receptors, such as TIM-3 and PD-L1, have been associated with poor survival and are implicated in hypomethylating agent resistance [7][8][9]. Furthermore, epigenetic gene silencing of activating immune receptor genes in AML has been observed; the expression of which can be shown to be rescued upon treatment with HDACi [10].…”

Section: Defining the Lsc: Function Over Formmentioning

confidence: 99%

A guide to epigenetics in leukaemia stem cells

Agrawal‐Singh,

Bagri,

Sakakini

et al. 2023

Molecular Oncology

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Leukaemia stem cells (LSCs) are the critical seed for the growth of haematological malignancies, driving the clonal expansion that enables disease initiation, relapse and often resistance. Specifically, they display inherent phenotypic and epigenetic plasticity resulting in complex heterogenic diseases. In this review, we discuss the key principles of deregulation of epigenetic processes that shape this disease evolution. We consider measures to define and quantify clonal heterogeneity, combining information from recent studies assessing mutational, transcriptional and epigenetic landscapes at single cell resolution in Myeloid Neoplasms (MN). We highlight the importance of integrating epigenetic and genetic information to better understand inter‐ and intra‐patient heterogeneity and discuss how this understanding further informs evolution and progression trajectories and subsequent clinical response in MN. Under this topic, we also discuss efforts to identify mechanisms of resistance, by longitudinal analysis of patient samples. Finally, we highlight how we might target these aberrant epigenetic processes for better therapeutic outcomes and to potentially eradicate LSCs.

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Upregulation of Tim‐3 is associated with poor prognosis in acute myeloid leukemia

Cited by 8 publications

References 54 publications

Identification and validation of a prognostic risk-scoring model based on the level of TIM-3 expression in acute myeloid leukemia

Identification and validation of a prognostic risk-scoring model based on the level of TIM-3 expression in acute myeloid leukemia

Checkpoint inhibition in hematologic malignancies

A guide to epigenetics in leukaemia stem cells

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