UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO

Goyama, Susumu; Schibler, Janet; Gasilina, Anjelika; Shrestha, Mahesh; Lin, Shuo; Link, Kevin A.; Chen, Jianjun; Whitman, Susan P.; Bloomfield, Clara D.; Nicolet, Deedra; Assi, Salam A.; Ptasińska, Anetta; Heidenreich, Olaf; Bonifer, Constanze; Kitamura, Toshio; Nassar, Nicolas; Mulloy, James C.

doi:10.1038/leu.2015.275

Cited by 57 publications

(47 citation statements)

References 75 publications

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“…We engineered human MLL-AF9- and AML-ETO-expressing cells by transducing MLL-AF9 and AML1-ETO into CB cells using retrovirus, as described previously. 22,38–40 Cells were cultured in IMDM media containing 20% BIT9500 (STEMCELL Technologies) and 10 ng/ml human stem cell factor, thrombopoietin, FLT3 ligand, interleukin-3 and interleukin-6, as described previously. 41,42 …”

Section: Methodsmentioning

confidence: 99%

Protease-activated receptor-1 inhibits proliferation but enhances leukemia stem cell activity in acute myeloid leukemia

et al. 2016

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Eradication of leukemia stem cells (LSCs) is the ultimate goal of treating acute myeloid leukemia (AML). We recently showed that the combined loss of Runx1/Cbfb inhibited the development of MLL-AF9-induced AML. However, c-Kit+/Gr-1− cells remained viable in Runx1/Cbfb-deleted cells, indicating that suppressing RUNX activity may not eradicate the most immature LSCs. In this study, we found upregulation of several hemostasis-related genes, including the thrombin-activatable receptor PAR-1 (protease-activated receptor-1), in Runx1/Cbfb-deleted MLL-AF9 cells. Similar to the effect of Runx1/Cbfb deletion, PAR-1 overexpression induced CDKN1A/p21 expression and attenuated proliferation in MLL-AF9 cells. To our surprise, PAR-1 deficiency also prevented leukemia development induced by a small number of MLL-AF9 leukemia stem cells (LSCs) in vivo. PAR-1 deficiency also reduced leukemogenicity of AML1-ETO-induced leukemia. Re-expression of PAR-1 in PAR-1-deficient cells combined with a limiting-dilution transplantation assay demonstrated the cell-dose-dependent role of PAR-1 in MLL-AF9 leukemia: PAR-1 inhibited rapid leukemic proliferation when there were a large number of LSCs, while a small number of LSCs required PAR-1 for their efficient growth. Mechanistically, PAR-1 increased the adherence properties of MLL-AF9 cells and promoted their engraftment to bone marrow. Taken together, these data revealed a multifaceted role for PAR-1 in leukemogenesis, and highlight this receptor as a potential target to eradicate primitive LSCs in AML.

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Section: Methodsmentioning

confidence: 99%

Protease-activated receptor-1 inhibits proliferation but enhances leukemia stem cell activity in acute myeloid leukemia

et al. 2016

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“…These NP 366-374 /D b CD103 + T RM also overexpress Ubash3b, a phosphatase suppressor of T cell signaling (FDR adj. p-val = 0.00294) [59,60].…”

Section: Distinct Transcriptional Programs Of Np 366-374 /D B and Pa mentioning

confidence: 97%

TCR‐pMHC encounter differentially regulates transcriptomes of tissue‐resident CD8 T cells

Yoshizawa

Keskin

et al. 2017

Eur J Immunol

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To investigate the role of TCR-pMHC interaction in regulating lung CD8 tissue-resident T cell (T ) differentiation, polyclonal responses were compared against NP /D and PA /D , two immunodominant epitopes that arise during influenza A infection in mice. Memory niches distinct from iBALTs develop within the lamina propria, supporting CD103 and CD103 CD8 T generation and intraepithelial translocation. Gene set enrichment analysis (GSEA) and weighted gene co-expression network analysis (WGCNA) identify dominant TCR, adherens junction, RIG-I-like and NOD-like pattern recognition receptor as well as TGF-β signaling pathways and memory signatures among PA /D T cells consistent with T resident memory (T ) status. In contrast, NP /D T cells exhibit enrichment of effector signatures, upregulating pro-inflammatory mediators even among T . While NP /D T cells manifest transcripts linked to canonical exhaustion pathways, PA /D T cells exploit P2rx7 purinoreceptor attenuation. The NP /D CD103 subset expresses the antimicrobial lactotransferrin whereas PA /D CD103 utilizes pore-forming mpeg-1, with <22% of genes correspondingly upregulated in CD103 (or CD103 ) subsets of both specificities. Thus, TCR-pMHC interactions among T and antigen presenting cells in a tissue milieu strongly impact CD8 T cell biology.

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“…From this point of view, CBL may act mainly as a tumor suppressor in the pathogenesis of human cancers. For example, some studies revealed a role of CBL in restricting tumor cell proliferation and invasion [35, 36]. Conversely, CBL is regarded as a proto-oncogene with numerous mutations and important roles in some cancers, including myeloid neoplasms [37], colorectal cancer [38] and glioma [19].…”

Section: Discussionmentioning

confidence: 99%

miR-124-3p functions as a tumor suppressor in breast cancer by targeting CBL

Chen

et al. 2016

BMC Cancer

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BackgroundThe origin and development of breast cancer remain complex and obscure. Recently, microRNA (miRNA) has been identified as an important regulator of the initiation and progression of breast cancer, and some studies have shown the essential role of miR-124-3p as a tumor suppressor in breast tumorigenesis. However, the detailed role of miR-124-3p in breast cancer remains poorly understood.MethodsQuantitative RT-PCR and western blotting assays were used to measure miR-124-3p and CBL expression levels in breast cancer tissues, respectively. Luciferase reporter assay was employed to validate the direct targeting of CBL by miR-124-3p. Cell proliferation and invasion assays were performed to analyze the biological functions of miR-124-3p and CBL in breast cancer cells.ResultsIn the present study, we found that miR-124-3p was consistently downregulated in breast cancer tissues. Moreover, we showed that miR-124-3p significantly suppressed the proliferation and invasion of breast cancer cells. In addition, we investigated the molecular mechanism through which miR-124-3p contributes to breast cancer tumorigenesis and identified CBL (Cbl proto-oncogene, E3 ubiquitin protein ligase) as a direct target gene of miR-124-3p. Moreover, we found that ectopic expression of CBL can attenuate the inhibitory effect of miR-124-3p on cell proliferation and invasion in breast cancer cells.ConclusionsThis study identified a new regulatory axis in which miR-124-3p and CBL regulate the proliferation and invasion of breast cancer cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2862-4) contains supplementary material, which is available to authorized users.

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UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO

Cited by 57 publications

References 75 publications

Protease-activated receptor-1 inhibits proliferation but enhances leukemia stem cell activity in acute myeloid leukemia

Protease-activated receptor-1 inhibits proliferation but enhances leukemia stem cell activity in acute myeloid leukemia

TCR‐pMHC encounter differentially regulates transcriptomes of tissue‐resident CD8 T cells

miR-124-3p functions as a tumor suppressor in breast cancer by targeting CBL

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