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From Pathology to Precision Medicine in Anaplastic Large Cell Lymphoma Expressing Anaplastic Lymphoma Kinase (ALK+ ALCL).

ABSTRACT: Anaplastic large cell lymphoma expressing anaplastic lymphoma kinase (ALK+ ALCL) is a distinct subtype of non-Hodgkin lymphoma. In this review, we discuss the historical findings that led to its classification as a unique disease, despite its varied clinical presentation and histology. We discuss the molecular mechanisms underlying ALK+ ALCL pathology and the questions that remain in the field. Finally, we visit how decades of ALK+ ALCL research has yielded more precise drugs that hold promise for the future.

SUBMITTER: Werner MT

PROVIDER: S-EPMC5664077 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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From Pathology to Precision Medicine in Anaplastic Large Cell Lymphoma Expressing Anaplastic Lymphoma Kinase (ALK+ ALCL).

Werner Michael T MT Zhang Qian Q Wasik Mariusz A MA

Cancers 20171016 10

Anaplastic large cell lymphoma expressing anaplastic lymphoma kinase (ALK+ ALCL) is a distinct subtype of non-Hodgkin lymphoma. In this review, we discuss the historical findings that led to its classification as a unique disease, despite its varied clinical presentation and histology. We discuss the molecular mechanisms underlying ALK+ ALCL pathology and the questions that remain in the field. Finally, we visit how decades of ALK+ ALCL research has yielded more precise drugs that hold promise f ...[more]

PMID: 29035291

Similar Datasets

Precision therapy with anaplastic lymphoma kinase inhibitor ceritinib in ALK-rearranged anaplastic large cell lymphoma.

Project description:BackgroundMore than 80% of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) patients harbor the (nucleophosmin) NPM1-ALK fusion gene t(2;5) chromosomal translocation. We evaluated the preclinical and clinical efficacy of ceritinib treatment of this aggressive lymphoma.Materials and methodsWe studied the effects of ceritinib treatment in NPM1-ALK+ T-cell lymphoma cell lines in vitro and on tumor size and survival advantage in vivo utilizing tumor xenografts. We treated an NPM1-ALK+ ALCL patient with ceritinib. We reviewed all hematologic malignancies profiled by a large hybrid-capture next-generation sequencing (NGS)-based comprehensive genomic profiling assay for ALK alterations.ResultsIn our in vitro experiments, ceritinib inhibited constitutive activation of the fusion kinase NPM1-ALK and downstream effector molecules STAT3, AKT, and ERK1/2, and induced apoptosis of these lymphoma cell lines. Cell cycle analysis following ceritinib treatment showed G0/G1 arrest with a concomitant decrease in the percentage of cells in S and G2/M phases. Further, treatment with ceritinib in the NPM1-ALK+ ALCL xenograft model resulted in tumor regression and improved survival. Of 19 272 patients with hematopoietic diseases sequenced, 58 patients (0.30%) harbored ALK fusions that include histiocytic disorders, multiple myeloma, B-cell neoplasms, Castleman's disease, and juvenile xanthogranuloma. A multiple relapsed NPM1-ALK+ ALCL patient treated with ceritinib achieved complete remission with ongoing clinical benefit to date, 5 years after initiation of therapy.ConclusionsThis ceritinib translational study in NPM1-ALK+ ALCL provides a strong rationale for a prospective study of ceritinib in ALK+ T-cell lymphomas and other ALK+ hematologic malignancies.

| S-EPMC8271116 | biostudies-literature

ALK+ Anaplastic Large Cell Lymphoma (ALCL)-Derived Exosomes Carry ALK Signaling Proteins and Interact with Tumor Microenvironment

Project description:Simple Summary ALK+ anaplastic large cell lymphoma (ALK+ ALCL) is a distinct type of aggressive non-Hodgkin lymphoma of T-cell origin, which is characterized by overexpression and activation of ALK kinase due to chromosomal translocations of the gene. The most frequent chromosomal aberration is the t(2;5) resulting in the NPM-ALK chimeric protein, which exerts its oncogenic functions through activation of multiple oncogenic pathways. Exosomes, the best characterized type of extracellular vesicles, are secreted from the tumor cells, thus transferring signals to other cells that uptake exosomes. In this study, we demonstrate that ALK+ ALCL cells secrete exosomes that carry critical molecules of ALK signaling, which can be taken up by other cells with significant biologic effects including functional interactions with tumor microenvironment cells, which may contribute to tumor aggressiveness and possibly resistance to treatment. Abstract The oncogenic pathways activated by the NPM-ALK chimeric kinase of ALK+ anaplastic large cell lymphoma (ALCL) are well characterized; however, the potential interactions of ALK signaling with the microenvironment are not yet known. Here we report that ALK+ ALCL-derived exosomes contain critical components of ALK signaling as well as CD30, and that exosome uptake by lymphoid cells led to increased proliferation and expression of critical antiapoptotic proteins by the recipient cells. The bone marrow fibroblasts highly uptake ALK+ ALCL-derived exosomes and acquire a cancer-associated fibroblast (CAF) phenotype. Moreover, exosome-mediated activation of stromal cells altered the cytokine profile of the microenvironment. These interactions may contribute to tumor aggressiveness and possibly resistance to treatment.

| S-EPMC9221431 | biostudies-literature

Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)+ and ALK- anaplastic large-cell lymphoma.

Project description:Aberrant anaplastic lymphoma kinase (ALK) expression is a defining feature of many human cancers and was identified first in anaplastic large-cell lymphoma (ALCL), an aggressive non-Hodgkin T-cell lymphoma. Since that time, many studies have set out to identify the mechanisms used by aberrant ALK toward tumorigenesis. We have identified a distinct profile of micro-RNAs (miRNAs) that characterize ALCL; furthermore, this profile distinguishes ALK(+) from ALK(-) subtypes, and thus points toward potential mechanisms of tumorigenesis induced by aberrant ALK. Using a nucleophosmin-ALK transgenic mouse model as well as human primary ALCL tumor tissues and human ALCL-derived cell lines, we reveal a set of overlapping deregulated miRNAs that might be implicated in the development and progression of ALCL. Importantly, ALK(+) and ALK(-) ALCL could be distinguished by a distinct profile of "oncomirs": Five members of the miR-17-92 cluster were expressed more highly in ALK(+) ALCL, whereas miR-155 was expressed more than 10-fold higher in ALK(-) ALCL. Moreover, miR-101 was down-regulated in all ALCL model systems, but its forced expression attenuated cell proliferation only in ALK(+) and not in ALK(-) cell lines, perhaps suggesting different modes of ALK-dependent regulation of its target proteins. Furthermore, inhibition of mTOR, which is targeted by miR-101, led to reduced tumor growth in engrafted ALCL mouse models. In addition to future therapeutical and diagnostic applications, it will be of interest to study the physiological implications and prognostic value of the identified miRNA profiles.

| S-EPMC2941277 | biostudies-other

Novel Molecular Challenges in Targeting Anaplastic Lymphoma Kinase in ALK-Expressing Human Cancers.

Project description:Targeting anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase receptor initially identified as a potent oncogenic driver in anaplastic large-cell lymphoma (ALCL) in the form of nucleophosmin (NPM)-ALK fusion protein, using tyrosine kinase inhibitors has shown to be a promising therapeutic approach for ALK-expressing tumors. However, clinical resistance to ALK inhibitors invariably occurs, and the molecular mechanisms are incompletely understood. Recent studies have clearly shown that clinical resistance to ALK inhibitors is a multifactorial and complex mechanism. While few of the mechanisms of clinical resistance to ALK inhibitors such as gene mutation are well known, there are others that are not well covered. In this review, the molecular mechanisms of cancer stem cells in mediating resistance to ALK inhibitors as well as the current understanding of the molecular challenges in targeting ALK in ALK-expressing human cancers will be discussed.

| S-EPMC5704166 | biostudies-literature

The Pathological Spectrum of Systemic Anaplastic Large Cell Lymphoma (ALCL).

Project description:Anaplastic large cell lymphoma (ALCL) represents a group of malignant T-cell lymphoproliferations that share morphological and immunophenotypical features, namely strong CD30 expression and variable loss of T-cell markers, but differ in clinical presentation and prognosis. The recognition of anaplastic lymphoma kinase (ALK) fusion proteins as a result of chromosomal translocations or inversions was the starting point for the distinction of different subgroups of ALCL. According to their distinct clinical settings and molecular findings, the 2016 revised World Health Organization (WHO) classification recognizes four different entities: systemic ALK-positive ALCL (ALK+ ALCL), systemic ALK-negative ALCL (ALK− ALCL), primary cutaneous ALCL (pC-ALCL), and breast implant-associated ALCL (BI-ALCL), the latter included as a provisional entity. ALK is rearranged in approximately 80% of systemic ALCL cases with one of its partner genes, most commonly NPM1, and is associated with favorable prognosis, whereas systemic ALK− ALCL shows heterogeneous clinical, phenotypical, and genetic features, underlining the different oncogenesis between these two entities. Recognition of the pathological spectrum of ALCL is crucial to understand its pathogenesis and its boundaries with other entities. In this review, we will focus on the morphological, immunophenotypical, and molecular features of systemic ALK+ and ALK− ALCL. In addition, BI-ALCL will be discussed.

| S-EPMC5923362 | biostudies-literature

Identification of C/EBP? target genes in ALK+ anaplastic large cell lymphoma (ALCL) by gene expression profiling and chromatin immunoprecipitation.

Project description:C/EBP? (CCAAT enhancer binding protein) is a transcription factor that plays a crucial role in survival and transformation of ALK+ anaplastic large cell lymphoma (ALCL). The aim of this study was to identify the downstream targets of C/EBP? responsible for ALK-mediated oncogenesis. C/EBP? was knocked down in ALK+ ALCL cell lines with a C/EBP?-shRNA, followed by gene expression profiling (GEP). GEP analysis revealed a reproducible signature of genes that were significantly regulated by C/EBP?. Classification into biological categories revealed overrepresentation of genes involved in the immune response, apoptosis and cell proliferation. Transcriptional regulation by C/EBP? was found in 6 of 11 (BCL2A1, G0S2, TRIB1, S100A9, DDX21 and DDIT4) genes investigated by chromatin immunoprecipitation. We demonstrated that BCL2A1, G0S2 and DDX21 play a crucial role in survival and proliferation of ALK+ ALCL cells. DDX21, a gene involved in rRNA biogenesis, was found differentially overexpressed in primary ALK+ ALCL cases. All three candidate genes were validated in primary ALCL cases by either immunohistochemistry or RT-qPCR. In conclusion, we identified and validated several key C/EBP?-regulated genes with major impact on survival and cell growth in ALK+ ALCL, supporting the central role of C/EBP? in ALK-mediated oncogenesis.

| S-EPMC3669320 | biostudies-literature

BRG1 and NPM-ALK Are Co-Regulated in Anaplastic Large-Cell Lymphoma; BRG1 Is a Potential Therapeutic Target in ALCL.

Project description:Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy driven in many cases by the product of a chromosomal translocation, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). NPM-ALK activates a plethora of pathways that drive the hallmarks of cancer, largely signalling pathways normally associated with cytokine and/or T-cell receptor-induced signalling. However, NPM-ALK is also located in the nucleus and its functions in this cellular compartment for the most part remain to be determined. We show that ALCL cell lines and primary patient tumours express the transcriptional activator BRG1 in a NPM-ALK-dependent manner. NPM-ALK regulates expression of BRG1 by post-translational mechanisms dependent on its kinase activity, protecting it from proteasomal degradation. Furthermore, we show that BRG1 drives a transcriptional programme associated with cell cycle progression. In turn, inhibition of BRG1 expression with specific shRNA decreases cell viability, suggesting that it may represent a key therapeutic target for the treatment of ALCL.

| S-EPMC8750310 | biostudies-literature

Involvement of Grb2 adaptor protein in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-mediated signaling and anaplastic large cell lymphoma growth.

Project description:Most anaplastic large cell lymphomas (ALCL) express oncogenic fusion proteins derived from chromosomal translocations or inversions of the anaplastic lymphoma kinase (ALK) gene. Frequently ALCL carry the t(2;5) translocation, which fuses the ALK gene to the nucleophosmin (NPM1) gene. The transforming activity mediated by NPM-ALK fusion induces different pathways that control proliferation and survival of lymphoma cells. Grb2 is an adaptor protein thought to play an important role in ALK-mediated transformation, but its interaction with NPM-ALK, as well as its function in regulating ALCL signaling pathways and cell growth, has never been elucidated. Here we show that active NPM-ALK, but not a kinase-dead mutant, bound and induced Grb2 phosphorylation in tyrosine 160. An intact SH3 domain at the C terminus of Grb2 was required for Tyr(160) phosphorylation. Furthermore, Grb2 did not bind to a single region but rather to different regions of NPM-ALK, mainly Tyr(152-156), Tyr(567), and a proline-rich region, Pro(415-417). Finally, shRNA knockdown experiments showed that Grb2 regulates primarily the NPM-ALK-mediated phosphorylation of SHP2 and plays a key role in ALCL cell growth.

| S-EPMC2924075 | biostudies-literature

ALK-positive anaplastic large cell lymphoma in adults.

Project description:ALK-positive anaplastic large cell lymphoma (ALCL) represents approximately 6-7% of the mature T-cell lymphomas. This subtype contains a translocation between the ALK gene on chromosome 2 and one of several other genes that together form an oncogene. The most frequent translocation is t(2;5) which combines ALK with NPM1. This lymphoma has a median age of 34 years, is more common in males, and is in advanced stage at the time of diagnosis in most patients. ALK-positive ALCL is the most curable of the peripheral T-cell lymphomas. The CHOP regimen has been most frequently used, but results are improved with the substitution of brentuximab vedotin for vincristine (BV-CHP) and the addition of etoposide (CHOEP), with BV-CHP being favored. Salvage therapies include allogeneic or autologous bone marrow transplantation, BV, if not used as part of the primary therapy, and ALK inhibitors. The latter are very active and likely to be incorporated into the primary therapy.

| S-EPMC10467138 | biostudies-literature

Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK).

Project description:We present the development of the first small molecule degraders that can induce anaplastic lymphoma kinase (ALK) degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines. These degraders were developed through conjugation of known pyrimidine-based ALK inhibitors, TAE684 or LDK378, and the cereblon ligand pomalidomide. We demonstrate that in some cell types degrader potency is compromised by expression of drug transporter ABCB1. In addition, proteomic profiling demonstrated that these compounds also promote the degradation of additional kinases including PTK2 (FAK), Aurora A, FER, and RPS6KA1 (RSK1).

| S-EPMC6294449 | biostudies-other

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