The Potent Oncogene NPM-ALK Mediates Malignant Transformation of Normal Human CD4+ T Lymphocytes

Zhang, Qian; Wei, Fang; Wang, Hong Yi; Liu, Xiaobin; Roy, Darshan; Xiong, Qun-Bin; Jiang, Shuguang; Medvec, Andrew; Danet-Desnoyers, Gwenn; Watt, Christopher D.; Tomczak, Ewa; Kalos, Michael; Riley, James L.; Wasik, Mariusz A.

doi:10.1016/j.ajpath.2013.08.030

Cited by 31 publications

(31 citation statements)

References 27 publications

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“…It is well established that ALK fusions are powerful oncogenes {Barreca, 2011 #618;Zhang, 2013 #1260} leading to the constitutive activation of JAK/STAT, PI3K/AKT, Ras/ERK1-2 and PLC-γ pathways {Barreca, 2011 #618;Tabbo, 2012 #13783}. Moreover, ALK chimera can interact with TRAF2 and modulate the CD30-mediate activation of NFkB {Horie, 2004 #805}.…”

Section: Discussionmentioning

confidence: 99%

A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation

et al. 2014

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Although Anaplastic Large Cell Lymphomas (ALCL) carrying Anaplastic Lymphoma Kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human Patient Derived Tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and of NFkB pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells lacking PRDM1/Blimp-1 and with c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to down-regulation of p50/p52 and lymphoma growth inhibition. Moreover a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Moreover, a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, but the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable to validate the role of druggable molecules, predict therapeutic responses and are helpful tools for the implementation of patient specific therapies.

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Section: Discussionmentioning

confidence: 99%

A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation

et al. 2014

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“…The gain of expression of oncogenes or the loss of expression of tumor suppressors has been shown to regulate immune checkpoints [35–38]. The upregulation of PD-L1 and related immunosuppressive pathways in mouse models of epidermal growth factor receptor (EGFR)-driven lung cancer was accompanied by decreases in cytotoxic tumor infiltrating lymphocytes (CTLs) and increases in T cell exhaustion [36].…”

Section: Oncogenes Regulate the Immune Responsementioning

confidence: 99%

MYC: Master Regulator of Immune Privilege

Casey

Baylot

Felsher

2017

Trends in Immunology

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Cancers are often initiated by genetic events that activate proto-oncogenes or inactivate tumor suppressor genes. These events are also critical for sustained tumor cell proliferation and survival, a phenomenon described as oncogene addiction. In addition to this cell intrinsic role, recent evidence indicates that oncogenes also directly regulate immune responses, leading to immunosuppression. Expression of many oncogenes, or loss of tumor suppressors, indeed induces the expression of immune checkpoints including PD-L1, which regulate the immune response. Here, we discuss how oncogenes, and in particular MYC, suppress immune surveillance and how oncogene-targeted therapies may restore the immune response against tumors.

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“…The assay was performed as described previously (27). Specifications of this experiment are detailed in the Supplementary Methods section.…”

Section: Western Blot Analysismentioning

confidence: 99%

The Addition of the BTK Inhibitor Ibrutinib to Anti-CD19 Chimeric Antigen Receptor T Cells (CART19) Improves Responses against Mantle Cell Lymphoma

Ruella

Kenderian

Shestova

et al. 2016

Clinical Cancer Research

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158

124

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Purpose: Responses to therapy with chimeric antigen receptor T cells recognizing CD19 (CART19, CTL019) may vary by histology. Mantle cell lymphoma (MCL) represents a B-cell malignancy that remains incurable despite novel therapies such as the BTK inhibitor ibrutinib, and where data from CTL019 therapy are scant. Using MCL as a model, we sought to build upon the outcomes from CTL019 and from ibrutinib therapy by combining these in a rational manner.Experimental Design: MCL cell lines and primary MCL samples were combined with autologous or normal donor-derived anti-CD19 CAR T cells along with ibrutinib. The effect of the combination was studied in vitro and in mouse xenograft models.Results: MCL cells strongly activated multiple CTL019 effector functions, and MCL killing by CTL019 was further enhanced in the presence of ibrutinib. In a xenograft MCL model, we showed superior disease control in the CTL019-as compared with ibrutinib-treated mice (median survival not reached vs. 95 days, P < 0.005) but most mice receiving CTL019 monotherapy eventually relapsed. Therefore, we added ibrutinib to CTL019 and showed that 80% to 100% of mice in the CTL019 þ ibrutinib arm and 0% to 20% of mice in the CTL019 arm, respectively, remained in long-term remission (P < 0.05).Conclusions: Combining CTL019 with ibrutinib represents a rational way to incorporate two of the most recent therapies in MCL. Our findings pave the way to a two-pronged therapeutic strategy in patients with MCL and other types of B-cell lymphoma.

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The Potent Oncogene NPM-ALK Mediates Malignant Transformation of Normal Human CD4+ T Lymphocytes

Cited by 31 publications

References 27 publications

A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation

A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation

MYC: Master Regulator of Immune Privilege

The Addition of the BTK Inhibitor Ibrutinib to Anti-CD19 Chimeric Antigen Receptor T Cells (CART19) Improves Responses against Mantle Cell Lymphoma

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