scholarly journals Ablation of oncogenic ALK is a viable therapeutic approach for anaplastic large-cell lymphomas

Blood ◽  
2006 ◽  
Vol 107 (2) ◽  
pp. 689-697 ◽  
Author(s):  
Roberto Piva ◽  
Roberto Chiarle ◽  
Andrea D. Manazza ◽  
Riccardo Taulli ◽  
William Simmons ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Cellular Transformation ◽  
Large Cell ◽  
Tumor Growth Inhibition ◽  
Chromosome Translocations ◽  
Anaplastic Lymphoma ◽  
Lymphoid Neoplasia ◽  
Downstream Effectors

Abstract Anaplastic large-cell lymphomas (ALCLs) carry chromosome translocations in which the anaplastic lymphoma kinase (ALK) gene is fused to several partners, most frequently, the NPM1 gene. We have demonstrated that the constitutive activation of ALK fusion proteins results in cellular transformation and lymphoid neoplasia. Herein, we specifically down-regulated ALK protein expression by using small hairpin RNA (shRNA) targeting a sequence coding for the catalytic domain of ALK. The ablation of ALK leads to the down-modulation of known ALK downstream effectors, cell growth arrest, and reversion of the transformed phenotype of ALK+ mouse embryonic fibroblasts in vitro and in vivo. In human ALCL cells lentiviral-mediated ALK knock-down leads to G1 cell-cycle arrest and apoptosis in vitro and tumor growth inhibition and regression in vivo. Using a specific approach we have demonstrated that the survival and growth of ALK+ ALCLs are strictly dependent on ALK activation and signaling. Therefore, ALK is a viable target for therapeutic intervention and its inactivation might represent a pivotal approach for the treatment of ALK lymphomas and other ALK-dependent human tumors.

scholarly journals Synergistic Drug Combinations Prevent Resistance in ALK+ Anaplastic Large Cell Lymphoma

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4422
Author(s):  
Giulia Arosio ◽  
Geeta G. Sharma ◽  
Matteo Villa ◽  
Mario Mauri ◽  
Ilaria Crespiatico ◽  
...  
Keyword(s):  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Drug Combinations ◽  
Tumor Growth Inhibition ◽  
Anaplastic Lymphoma ◽  
Alk Inhibitor ◽  
Large Cell Lymphoma

Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma characterized by expression of the oncogenic NPM/ALK fusion protein. When resistant or relapsed to front-line chemotherapy, ALK+ ALCL prognosis is very poor. In these patients, the ALK inhibitor crizotinib achieves high response rates, however 30–40% of them develop further resistance to crizotinib monotherapy, indicating that new therapeutic approaches are needed in this population. We here investigated the efficacy of upfront rational drug combinations to prevent the rise of resistant ALCL, in vitro and in vivo. Different combinations of crizotinib with CHOP chemotherapy, decitabine and trametinib, or with second-generation ALK inhibitors, were investigated. We found that in most cases combined treatments completely suppressed the emergence of resistant cells and were more effective than single drugs in the long-term control of lymphoma cells expansion, by inducing deeper inhibition of oncogenic signaling and higher rates of apoptosis. Combinations showed strong synergism in different ALK-dependent cell lines and better tumor growth inhibition in mice. We propose that drug combinations that include an ALK inhibitor should be considered for first-line treatments in ALK+ ALCL.

scholarly journals Super-enhancer-based identification of a BATF3/IL-2R−module reveals vulnerabilities in anaplastic large cell lymphoma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Huan-Chang Liang ◽  
Mariantonia Costanza ◽  
Nicole Prutsch ◽  
Mark W. Zimmerman ◽  
Elisabeth Gurnhofer ◽  
...  
Keyword(s):  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Breast Implant ◽  
Large Cell ◽  
Antibody Drug Conjugate ◽  
Anaplastic Lymphoma ◽  
Super Enhancer ◽  
Large Cell Lymphoma

AbstractAnaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL.

Molecular Biology of Anaplastic Lymphoma Kinase–Positive Anaplastic Large-Cell Lymphoma

2002 ◽  
Vol 20 (17) ◽  
pp. 3691-3702 ◽  
Author(s):  
Jeffery L. Kutok ◽  
Jon C. Aster
Keyword(s):  
T Cell ◽  
Anaplastic Large Cell Lymphoma ◽  
Anaplastic Lymphoma Kinase ◽  
Cell Lymphoma ◽  
Cellular Transformation ◽  
Large Cell ◽  
Null Cell ◽  
Anaplastic Lymphoma ◽  
Downstream Effectors ◽  
Large Cell Lymphoma

ABSTRACT: Anaplastic large-cell lymphoma (ALCL) provides an excellent example of how molecular insights into tumor pathogenesis are influencing and improving tumor classification. ALCL was described initially as a subtype of T-cell/null-cell lymphoma characterized by unusual tumor cell morphology and the expression of CD30. However, it was soon recognized that a subset of ALCLs contained chromosomal translocations involving anaplastic lymphoma kinase (ALK), a novel receptor tyrosine kinase gene. These rearrangements create chimeric genes encoding self-associating, constitutively active ALK fusion proteins that activate a number of downstream effectors, including phospholipase C-gamma, phosphoinositol 3'-kinase, RAS, and signal transducer and activator of transcription proteins, all of which seem potentially important in cellular transformation. Not all tumors classified as ALCLs have ALK rearrangements and, conversely, ALK rearrangements occur in lymphomas of widely varying morphology. Hence, only molecular markers can reliably identify ALK+ ALCL. The importance of doing so is reflected by clinical studies suggesting that ALK+ ALCLs have a significantly better prognosis than other aggressive peripheral T-cell or B-cell lymphomas, including ALK− ALCLs. The unique molecular pathogenesis of ALK+ ALCL is likely to lead to novel therapeutic approaches directed at specific inhibition of ALK or downstream effectors.

Bcl-XL down-regulation suppresses the tumorigenic potential of NPM/ALK in vitro and in vivo

Blood ◽  
2004 ◽  
Vol 103 (7) ◽  
pp. 2787-2794 ◽  
Author(s):  
Addolorata Maria Luce Coluccia ◽  
Silvia Perego ◽  
Loredana Cleris ◽  
Rosalind Helen Gunby ◽  
Lorena Passoni ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Systemic Disease ◽  
Large Cell ◽  
Common Finding ◽  
Down Regulation ◽  
Anaplastic Lymphoma ◽  
Mitochondrial Homeostasis ◽  
Tumorigenic Potential

Abstract Deregulated apoptosis is a common finding in tumorigenesis. The oncogenic tyrosine kinase nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) delivers a strong survival signal in anaplastic large cell lymphomas (ALCLs). Although NPM/ALK activates multiple antiapoptotic pathways, the biologic relevance and therapeutic potential of more downstream apoptotic effectors are mostly unknown. In this report, the NPM/ALK-mediated induction of Bcl-XL (but not of Bcl-2) was identified in human ALCL-derived cells. NPM/ALK kinase activity was required to promote Bcl-XL expression and its protective effect on mitochondrial homeostasis. Down-regulation of Bcl-XL significantly reduced the antiapoptotic potential of NPM/ALK in both transformed murine Ba/F3 pro-B cells and human ALCL-derived KARPAS-299 cells. To elucidate the role of Bcl-XL in vivo, Ba/F3-NPM/ALK+ cells expressing a doxycycline (Dox)-inducible Bcl-XL antisense transgene (pTet-ON) were injected into nude mice. Doxycycline administration prevented a fatal systemic disease in 15 of 15 intravenously injected mice and the appearance of subcutaneous tumor xenografts in 9 of 12 mice; in vivo down-regulation of Bcl-XL was also documented. Our results show a pivotal role for Bcl-XL in ALK-mediated oncogenicity; a single protein placed downstream of a known oncogene can be crucial for the survival of neoplastic cells both in vitro and in vivo. Bcl-XL deserves further investigation as a possible therapeutic target in ALK+ ALCLs. (Blood. 2004;103:2787-2794)

ALK+ALCLs induce cutaneous, HMGB-1–dependent IL-8/CXCL8 production by keratinocytes through NF-κB activation

Blood ◽  
2012 ◽  
Vol 119 (20) ◽  
pp. 4698-4707 ◽  
Author(s):  
Emilie Dejean ◽  
Marianne Foisseau ◽  
Fréderic Lagarrigue ◽  
Laurence Lamant ◽  
Naïs Prade ◽  
...  
Keyword(s):  
High Mobility ◽  
Large Cell ◽  
Premetastatic Niche ◽  
Anaplastic Lymphoma ◽  
Number Of Patients ◽  
Skin Colonization ◽  
Cell Invasiveness ◽  
First Time

Abstract Anaplastic large-cell lymphomas (ALCLs) bearing the t(2;5) translocation (ALK+ALCLs) are frequently characterized by skin colonization and associated with a poor prognosis. Using conditional transgenic models of anaplastic lymphoma kinase–positive (ALK+) lymphomas and human ALK+ALCL cell lines, in the present study, we show that high-mobility-group box-1 (HMGB-1), a proinflammatory cytokine, is released by ALK+ cells, and demonstrate extracellular HMGB-1–stimulated secretion of the IL-8 chemokine by HaCaT keratinocytes through the involvement of MMP-9, PAR-2, and the NF-κB pathway. Furthermore, we demonstrate that, in vitro, IL-8 is able to induce the invasiveness of ALK+ cells, which express the IL-8 receptors CXCR1 and CXCR2. In vitro and in vivo, HMGB-1 inhibition achieved by glycyrrhizin treatment led to a drastic reduction in ALK+ cell invasiveness. The pathophysiological relevance of our observations was confirmed by demonstrating that the HMGB-1 and IL-8 receptors are expressed in ALK+ALCL biopsies. We have also shown that IL-8 secretion is correlated with leukemic dissemination of ALK+ cells in a significant number of patients. The results of the present study demonstrate for the first time a relationship among the pro-inflammatory mediators HMGB-1, MMP-9, PAR-2, and IL-8. We propose that these mediators create a premetastatic niche within the skin, thereby participating in ALK+ lymphoma epidermotropism.

scholarly journals Effective therapy for a murine model of human anaplastic large-cell lymphoma with the anti-CD30 monoclonal antibody, HeFi-1, does not require activating Fc receptors

Blood ◽  
2006 ◽  
Vol 108 (2) ◽  
pp. 705-710 ◽  
Author(s):  
Meili Zhang ◽  
Zhengsheng Yao ◽  
Zhuo Zhang ◽  
Kayhan Garmestani ◽  
Carolyn K. Goldman ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Murine Model ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Tumor Growth Inhibition ◽  
Wild Type ◽  
Large Cell Lymphoma

CD30 is a member of the tumor necrosis factor receptor family. Overexpression of CD30 on some neoplasms versus its limited expression on normal tissues makes this receptor a promising target for antibody-based therapy. Anaplastic large-cell lymphoma (ALCL) represents a heterogeneous group of aggressive non-Hodgkin lymphomas characterized by the strong expression of CD30. We investigated the therapeutic efficacy of HeFi-1, a mouse IgG1 monoclonal antibody, which recognizes the ligand-binding site on CD30, and humanized anti-Tac antibody (daclizumab), which recognizes CD25, in a murine model of human ALCL. The ALCL model was established by intravenous injection of karpas299 cells into nonobese diabetic/severe combined immuno-deficient (SCID/NOD) wild-type or SCID/NOD Fc receptor common γ chain–deficient (FcRγ–/–) mice. HeFi-1, given at a dose of 100 μg weekly for 4 weeks, significantly prolonged survival of the ALCL-bearing SCID/NOD wild-type and SCID/NOD FcRγ–/– mice (P < .01) as compared with the control groups. In vitro studies showed that HeFi-1 inhibited the proliferation of karpas299 cells, whereas daclizumab did not inhibit cell proliferation. We demonstrated that the expression of FcRγ on polymorphonuclear leukocytes and monocytes was not required for HeFi-1–mediated tumor growth inhibition in vivo, although it was required for daclizumab.

scholarly journals Functional proteogenomics reveals biomarkers and therapeutic targets in lymphomas

2017 ◽  
Vol 114 (25) ◽  
pp. 6581-6586 ◽  
Author(s):  
Delphine C. M. Rolland ◽  
Venkatesha Basrur ◽  
Yoon-Kyung Jeon ◽  
Carla McNeil-Schwalm ◽  
Damian Fermin ◽  
...  
Keyword(s):  
Cell Lines ◽  
Therapeutic Targets ◽  
Cancer Biomarkers ◽  
Large Cell ◽  
Primary Lymphoma ◽  
Anaplastic Lymphoma ◽  
Genome Wide ◽  
A Genome

Identification of biomarkers and therapeutic targets is a critical goal of precision medicine. N-glycoproteins are a particularly attractive class of proteins that constitute potential cancer biomarkers and therapeutic targets for small molecules, antibodies, and cellular therapies. Using mass spectrometry (MS), we generated a compendium of 1,091 N-glycoproteins (from 40 human primary lymphomas and cell lines). Hierarchical clustering revealed distinct subtype signatures that included several subtype-specific biomarkers. Orthogonal immunological studies in 671 primary lymphoma tissue biopsies and 32 lymphoma-derived cell lines corroborated MS data. In anaplastic lymphoma kinase-positive (ALK+) anaplastic large cell lymphoma (ALCL), integration of N-glycoproteomics and transcriptome sequencing revealed an ALK-regulated cytokine/receptor signaling network, including vulnerabilities corroborated by a genome-wide clustered regularly interspaced short palindromic screen. Functional targeting of IL-31 receptor β, an ALCL-enriched and ALK-regulated N-glycoprotein in this network, abrogated ALK+ALCL growth in vitro and in vivo. Our results highlight the utility of functional proteogenomic approaches for discovery of cancer biomarkers and therapeutic targets.

scholarly journals Repotrectinib (TPX-0005), effectively reduces growth of ALK driven neuroblastoma cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Diana Cervantes-Madrid ◽  
Joanna Szydzik ◽  
Dan Emil Lind ◽  
Marcus Borenäs ◽  
Mats Bemark ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Xenograft Model ◽  
Large Cell ◽  
Antitumor Effects ◽  
Gene Encoding ◽  
Anaplastic Lymphoma

AbstractNeuroblastoma is the most commonly diagnosed extracranial tumor in the first year of life. Approximately 9% of neuroblastoma patients present germline or somatic aberrations in the gene encoding for anaplastic lymphoma kinase (ALK). This increases in high-risk neuroblastomas, which have a 14% frequency of ALK aberrations at the time of diagnosis and show increasing numbers at relapse. Abrogating ALK activity with kinase inhibitors is employed as clinical therapy in malignancies such as non-small cell lung cancer and has shown good results in pediatric inflammatory myofibroblastic tumors and anaplastic large cell lymphomas. A phase I clinical trial of the first generation ALK inhibitor, crizotinib, in neuroblastoma patients showed modest results and suggested that further investigation was needed. Continuous development of ALK inhibitors has resulted in the third generation inhibitor repotrectinib (TPX-0005), which targets the active kinase conformations of ALK, ROS1 and TRK receptors. In the present study we investigated the effects of repotrectinib in a neuroblastoma setting in vitro and in vivo. Neuroblastoma cell lines were treated with repotrectinib to investigate inhibition of ALK and to determine its effect on proliferation. PC12 cells transfected with different ALK mutant variants were used to study the efficacy of repotrectinib to block ALK activation/signaling. The in vivo effect of repotrectinib was also analyzed in a neuroblastoma xenograft model. Our results show that repotrectinib is capable of inhibiting signaling activity of a range of ALK mutant variants found in neuroblastoma patients and importantly it exhibits strong antitumor effects in a xenograft model of neuroblastoma.

scholarly journals Pathobiology of ALK+ anaplastic large-cell lymphoma

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2259-2267 ◽  
Author(s):  
Hesham M. Amin ◽  
Raymond Lai
Keyword(s):  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Clinical Manifestations ◽  
Large Cell ◽  
Experimental Models ◽  
Lymphoid Cells ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma

Anaplastic large-cell lymphoma (ALCL) was initially recognized on the basis of morphologic features and the consistent expression of CD30. It then became evident that the majority of these tumors are derived from lymphoid cells of T or null immunophenotype. The subsequent finding that t(2;5)(p23;q35) occurs in 40% to 60% of ALCL patients established a distinct clinicopathologic entity. This chromosomal translocation induces the formation of the chimeric protein nucleophosmin–anaplastic lymphoma kinase (NPM-ALK), which possesses significant oncogenic potential resulting from the constitutive activation of the tyrosine kinase ALK. In addition to its specific pathophysiologic events, NPM-ALK–expressing lymphoma presents with consistent clinical manifestations. Only 13 years after the identification of NPM-ALK, tremendous progress has been made in our understanding of this molecule because of the relentless efforts of multiple investigators who have dissected its biologic roles using in vitro and in vivo experimental models. Several upstream modulators, cross-reacting oncogenes, and downstream effectors of NPM-ALK have been identified and characterized. Understanding these interacting oncogenic systems is expected to facilitate the design of new therapeutic strategies and agents. In this review, we briefly discuss ALCL and focus on NPM-ALK.

scholarly journals Activation of TORC1 Transcriptional Coactivator through MEKK1-induced Phosphorylation

2008 ◽  
Vol 19 (11) ◽  
pp. 4750-4761 ◽  
Author(s):  
Yeung-Tung Siu ◽  
Yick-Pang Ching ◽  
Dong-Yan Jin
Keyword(s):  
Mammalian Cells ◽  
Catalytic Domain ◽  
Nuclear Translocation ◽  
Bzip Transcription Factor ◽  
Transcriptional Coactivator ◽  
Downstream Effectors ◽  
Interleukin 1Α ◽  
Subsequent Activation

CREB is a prototypic bZIP transcription factor and a master regulator of glucose metabolism, synaptic plasticity, cell growth, apoptosis, and tumorigenesis. Transducers of regulated CREB activity (TORCs) are essential transcriptional coactivators of CREB and an important point of regulation on which various signals converge. In this study, we report on the activation of TORC1 through MEKK1-mediated phosphorylation. MEKK1 potently activated TORC1, and this activation was independent of downstream effectors MEK1/MEK2, ERK2, JNK, p38, protein kinase A, and calcineurin. MEKK1 induced phosphorylation of TORC1 both in vivo and in vitro. Expression of the catalytic domain of MEKK1 alone in cultured mammalian cells sufficiently caused phosphorylation and subsequent activation of TORC1. MEKK1 physically interacted with TORC1 and stimulated its nuclear translocation. An activation domain responsive to MEKK1 stimulation was mapped to amino acids 431–650 of TORC1. As a physiological activator of CREB, interleukin 1α triggered MEKK1-dependent phosphorylation of TORC1 and its consequent recruitment to the cAMP response elements in the interleukin 8 promoter. Taken together, our findings suggest a new mechanism for regulated activation of TORC1 transcriptional coactivator and CREB signaling.

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