Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia

Hu, Cheng-Long; Chen, Bingyi; Li, Zijuan; Yang, Tianjun; Xu, Chunhui; Yang, Ruirui; Yu, Peng; Zhao, Jingyao; Liu, Ting; Liu, Na; Shu, Bin; Zhang, Qunling; Song, Junhong; Fei, Ming-Yue; Zong, Li-Juan; Zhang, Jiaying; Wu, Jichuan; Chen, Shu-Bei; Wang, Yong; Chang, Binhe; Hou, Dan; Liu, Ping; Jiang, Yilun; Li, Xiya; Chen, Xinchi; Deng, Chuhan; Ren, Yi-Yi; Wang, Roujia; Jin, Jiacheng; Xue, Kai; Zhang, Ying; Du, Meirong; Shi, Jun; Wu, Lingyun; Chang, Chunkang; Shen, Shuhong; Chen, Zhu; Chen, Sai‐Juan; Liu, Xiaolong; Sun, Xiao Jian; Zheng, Mingyue; Wang, Lan

doi:10.1038/s41422-022-00735-6

Cited by 15 publications

(8 citation statements)

References 66 publications

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“…Hu et al. ( 50 ) demonstrated that SAP30 can interact with UHRF1 to promote the activation of the MYC signaling pathway and abnormal self-renewal of leukemia-initiating cells, resulting in the occurrence and development of acute myeloid leukemia and poor prognosis. The E2F family affects cell cycle progression, apoptosis, differentiation, and DNA damage repair ( 51 – 53 ).…”

Section: Discussionmentioning

confidence: 99%

Unraveling the enigma of B cells in diffuse large B-cell lymphoma: unveiling cancer stem cell-like B cell subpopulation at single-cell resolution

Liu,

Zheng,

Yang

et al. 2023

Front. Immunol.

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BackgroundDiffuse large B-cell lymphoma (DLBCL) represents the most prevalent form of aggressive non-Hodgkin lymphoma. Despite receiving standard treatment, a subset of patients undergoes refractory or recurrent cases, wherein the involvement of cancer stem cells (CSCs) could be significant.MethodsWe comprehensively characterized B cell subpopulations using single-cell RNA sequencing data from three DLBCL samples and one normal lymph tissue. The CopyKat R package was employed to assess the malignancy of B cell subpopulations based on chromosomal copy number variations. CIBERSORTx software was utilized to estimate the proportions of B cell subpopulations in 230 DLBCL tissues. Furthermore, we employed the pySCENIC to identify key transcription factors that regulate the functionality of B cell subpopulations. By employing CellphoneDB, we elucidated the interplay among tumor microenvironment components within the B cell subpopulations. Finally, we validated our findings through immunofluorescence experiments.ResultsOur analysis revealed a specific cancer stem cell-like B cell subpopulation exhibiting self-renewal and multilineage differentiation capabilities based on the exploration of B cell subpopulations in DLBCL and normal lymph tissues at the single-cell level. Notably, a high infiltration of cancer stem cell-like B cells correlated with a poor prognosis, potentially due to immune evasion mediated by low expression of major histocompatibility complex molecules. Furthermore, we identified key transcription factor regulatory networks regulated by HMGB3, SAP30, and E2F8, which likely played crucial roles in the functional characterization of the cancer stem cell-like B cell subpopulation. The existence of cancer stem cell-like B cells in DLBCL was validated through immunofluorescent staining. Finally, cell communication between B cells and tumor-infiltrating T cell subgroups provided further insights into the functional characterization of the cancer stem cell-like B cell subpopulation.ConclusionsOur research provides a systematic description of a specific cancer stem cell-like B cell subpopulation associated with a poor prognosis in DLBCL. This study enhances our understanding of CSCs and identifies potential therapeutic targets for refractory or recurrent DLBCL patients.

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Section: Discussionmentioning

confidence: 99%

Unraveling the enigma of B cells in diffuse large B-cell lymphoma: unveiling cancer stem cell-like B cell subpopulation at single-cell resolution

Liu,

Zheng,

Yang

et al. 2023

Front. Immunol.

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“…There was also an enrichment for the hallmark apoptosis pathway in VcKO TPT DPs with Mxd4 mRNA, encoding for a Myc antagonist that inhibits leukemogenesis, topping the list of DEGs (Fig. 4G) (Hurlin et al, 1996) (Hu et al, 2022). Among the other notable DEGs were Fos, Dusp1 and Tet2, which may explain one mechanism by which competition may regulate gene expression to promote survival (Fig.…”

Section: Inter-thymocyte Competition Suppresses T-all Development Fro...mentioning

confidence: 97%

Loss of thymocyte competition underlies the tumor suppressive functions of the E2a transcription factor in T lymphocyte acute lymphoblastic leukemia

Parriott

Hegermiller

Morman

et al. 2023

Preprint

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T lymphocyte acute lymphoblastic leukemia (T-ALL) is frequently associated with increased expression of the E protein transcription factor inhibitors TAL1 and LYL1. In mouse models, ectopic expression of Tal1 or Lyl1 in T cell progenitors or inactivation of E2a, is sufficient to predispose mice to develop T-ALL. How E2a suppresses thymocyte transformation is currently unknown. Here, we show that early deletion of E2a, prior to the DN3 stage, was required for robust leukemogenesis and was associated with alterations in thymus cellularity, T cell differentiation, and gene expression in immature CD4+CD8+ thymocytes. Introduction of wild-type thymocytes into mice with early deletion of E2a prevented leukemogenesis, or delayed disease onset, and impacted the expression of multiple genes associated with transformation and genome instability. Our data indicate that E2a suppresses leukemogenesis by promoting T cell development and enforcing inter-thymocyte competition, a mechanism that is emerging as a safeguard against thymocyte transformation. These studies have implications for understanding how multiple essential regulators of T cell development suppress T-ALL and support the hypothesis that thymus cellularity is a determinant of leukemogenesis.

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“…The second network included three proteins and is referred to as the NuRD complex. Two of these proteins function as deacetylases (SAP30, MTA2), and the proteins in this network modulate the effects of both p53 (MTA2) and STAT3 (GATAD2A) (Tables S7 and S8) [84,85]. The NuRD complex is a chromatin remodeling complex [86,87].…”

Section: Comparison Of Phosphoproteomic Profiles For Fab-m4/m5 Cells ...mentioning

confidence: 99%

Monocytic Differentiation of Human Acute Myeloid Leukemia Cells: A Proteomic and Phosphoproteomic Comparison of FAB-M4/M5 Patients with and without Nucleophosmin 1 Mutations

Selheim,

Aasebø,

Reikvam

et al. 2024

IJMS

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Even though morphological signs of differentiation have a minimal impact on survival after intensive cytotoxic therapy for acute myeloid leukemia (AML), monocytic AML cell differentiation (i.e., classified as French/American/British (FAB) subtypes M4/M5) is associated with a different responsiveness both to Bcl-2 inhibition (decreased responsiveness) and possibly also bromodomain inhibition (increased responsiveness). FAB-M4/M5 patients are heterogeneous with regard to genetic abnormalities, even though monocytic differentiation is common for patients with Nucleophosmin 1 (NPM1) insertions/mutations; to further study the heterogeneity of FAB-M4/M5 patients we did a proteomic and phosphoproteomic comparison of FAB-M4/M5 patients with (n = 13) and without (n = 12) NPM1 mutations. The proteomic profile of NPM1-mutated FAB-M4/M5 patients was characterized by increased levels of proteins involved in the regulation of endocytosis/vesicle trafficking/organellar communication. In contrast, AML cells without NPM1 mutations were characterized by increased levels of several proteins involved in the regulation of cytoplasmic translation, including a large number of ribosomal proteins. The phosphoproteomic differences between the two groups were less extensive but reflected similar differences. To conclude, even though FAB classification/monocytic differentiation are associated with differences in responsiveness to new targeted therapies (e.g., Bcl-2 inhibition), our results shows that FAB-M4/M5 patients are heterogeneous with regard to important biological characteristics of the leukemic cells.

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Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia

Cited by 15 publications

References 66 publications

Unraveling the enigma of B cells in diffuse large B-cell lymphoma: unveiling cancer stem cell-like B cell subpopulation at single-cell resolution

Unraveling the enigma of B cells in diffuse large B-cell lymphoma: unveiling cancer stem cell-like B cell subpopulation at single-cell resolution

Loss of thymocyte competition underlies the tumor suppressive functions of the E2a transcription factor in T lymphocyte acute lymphoblastic leukemia

Monocytic Differentiation of Human Acute Myeloid Leukemia Cells: A Proteomic and Phosphoproteomic Comparison of FAB-M4/M5 Patients with and without Nucleophosmin 1 Mutations

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