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Molecular Pathogenesis and Management of Anaplastic Large Cell Lymphoma

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (1 June 2022) | Viewed by 32088

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Dr. Vasiliki Leventaki

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Department of Pathology, Children’s Hospital of Wisconsin & Medical College of Wisconsin, Milwaukee, WI 53226, USA
Interests: pathogenesis of pediatric lymphomas; hematopathology; leukemia/lymphoma diagnosis; molecular pathology

Special Issue Information

Dear colleagues,

Anaplastic large cell lymphoma (ALCL) includes distinct subgroups of peripheral mature T-cell lymphomas defined by their strong expression of the CD30 antigen and commonly composed of large pleomorphic cells. The defined entities in the most recent 2017 World Health Organization classification of hematopoietic and lymphoid tissues include systemic ALK-positive (ALK+) and ALK-negative (ALK-) ALCL, cutaneous ALCL, and breast implant-associated ALCL. Each entity is defined based on distinct genetic aberrations, epidemiological characteristics, clinical presentations, and prognosis. The presence of an ALK rearrangement resulting in the aberrant expression of the ALK fusion oncoprotein is a genetically defining aberration for ALK+ ALCL, which more frequently affects children and young adults and has better prognosis compared to ALK- ALCL. Notably, within the ALK- ALCL group, subsets with mutually exclusive cytogenetic alterations have been identified (TP63r+, IRF4/DUSP22r+, and triple-negative ALCL) with prognostic implications. The cutaneous ALCL and breast implant-associated ALCL show characteristic clinical courses, presenting as noninvasive disease with excellent outcomes following complete excision or limited, localized treatment. The standard treatment for systemic ALCL is multiagent chemotherapy, while recent clinical trials have demonstrated a role for anti-CD30 immunotherapy. Specifically, in ALK+ ALCL, the clinical use of ALK inhibitors has shown promising results as a monotherapy or in combination with chemotherapy. Given the continuous progress surrounding novel immunotherapeutic strategies such as checkpoint inhibition, the prospect of effective immunotherapy could become a viable clinical intervention for patients with ALCL. This Special Issue will consist of papers discussing the advances in the understanding of the various mechanisms implicated in the pathogenesis of ALCL and their role in developing novel therapies and biomarkers for clinical benefit.

Prof. Vasiliki Leventaki
Guest Editor

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Keywords

anaplastic large cell lymphoma
ALK
therapies
epigenetics
CD30
crizotinib
checkpoint inhibitors
immune responses

Published Papers (10 papers)

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Research

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13 pages, 2802 KiB

Open AccessArticle

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

by Dimitrios Chioureas, Janina Beck, George Baltatzis, Ioulia Vardaki, Pedro Fonseca, Nikolaos Tsesmetzis, Francisco Vega, Vasiliki Leventaki, Aristides G. Eliopoulos, Elias Drakos, George Z. Rassidakis and Theocharis Panaretakis

Cancers 2022, 14(12), 2939; https://doi.org/10.3390/cancers14122939 - 14 Jun 2022

Cited by 2 | Viewed by 1817

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. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Management of Anaplastic Large Cell Lymphoma)

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12 pages, 2170 KiB

Open AccessArticle

Quantification of Minimal Disease by Digital PCR in ALK-Positive Anaplastic Large Cell Lymphoma: A Step towards Risk Stratification in International Trials?

by Christine Damm-Welk, Federica Lovisa, Giorgia Contarini, Jette Lüdersen, Elisa Carraro, Fabian Knörr, Jan Förster, Martin Zimmermann, Alessandra Sala, Luciana Vinti, Annalisa Tondo, Marta Pillon, Wilhelm Woessmann and Lara Mussolin

Cancers 2022, 14(7), 1703; https://doi.org/10.3390/cancers14071703 - 27 Mar 2022

Cited by 7 | Viewed by 2542

Abstract

Minimal disseminated and residual disease (MDD/MRD) analyzed by qualitative PCR for NPM-ALK fusion transcripts are validated prognostic factors in pediatric ALK-positive anaplastic large cell lymphoma (ALCL). Although potentially promising, MDD quantification by quantitative real-time PCR in international trials is technically challenging. Quantification of early MRD might further improve risk stratification. We aimed to assess droplet digital PCR for quantification of minimal disease in an inter-laboratory setting in a large cohort of 208 uniformly treated ALCL patients. Inter-laboratory quality control showed high concordance. Using a previously described cut-off of 30 copies NPM-ALK/10⁴ copies ABL1 (NCN) in bone marrow and peripheral blood, MDD quantification allowed identification of very high-risk patients (5-year PFS% 34 ± 5 for patients with ≥30 NCN compared to 74 ± 6 and 76 ± 5 for patients with negative or <30 NCN, respectively, p < 0.0001). While MRD positivity was confirmed as a prognostic marker for the detection of very high-risk patients in this large study, quantification of MRD fusion transcripts did not improve stratification. PFS% was 80 ± 5 and 73 ± 6 for MDD- and MRD-negative patients, respectively, versus 35 ± 10 and 16 ± 8 for MRD-positive patients with <30 and ≥30 NCN, p < 0.0001. Our results suggest that MDD quantification by dPCR enables improved patient stratification in international clinical studies and patient selection for early clinical trials already at diagnosis. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Management of Anaplastic Large Cell Lymphoma)

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15 pages, 3727 KiB

Open AccessArticle

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

by Gavin D. Garland, Stephen P. Ducray, Leila Jahangiri, Perla Pucci, G. A. Amos Burke, Jack Monahan, Raymond Lai, Olaf Merkel, Ana-Iris Schiefer, Lukas Kenner, Andrew J. Bannister and Suzanne D. Turner

Cancers 2022, 14(1), 151; https://doi.org/10.3390/cancers14010151 - 29 Dec 2021

Cited by 3 | Viewed by 2367

Abstract

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. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Management of Anaplastic Large Cell Lymphoma)

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13 pages, 11266 KiB

Open AccessArticle

The Leukemic Phase of ALK-Negative Anaplastic Large Cell Lymphoma Is Associated with CD7 Positivity, Complex Karyotype, TP53 Deletion, and a Poor Prognosis

by Lianqun Qiu, L. Jeffrey Medeiros, Guilin Tang, Mahsa Khanlari, Shaoying Li, Sergej Konoplev, Sa A. Wang, C. Cameron Yin, Joseph D. Khoury, Wei Wang, Roberto N. Miranda, Swaminathan Iyer, M. James You and Jie Xu

Cancers 2021, 13(24), 6316; https://doi.org/10.3390/cancers13246316 - 16 Dec 2021

Cited by 1 | Viewed by 2029

Abstract

Patients with anaplastic large cell lymphoma (ALCL) rarely develop a leukemic phase of the disease. The reported leukemic ALCL cases are almost all ALK-positive, which are frequently associated with small cell morphology, t(2;5)(p23;q35), and a poorer prognosis. Rare leukemic ALK-negative ALCL cases have been reported. In the present study, we investigated the clinical and pathologic features and outcomes of nine patients with leukemic ALK-negative ALCL and compared these features with 39 patients without leukemic disease. Compared with the non-leukemic ALK-negative ALCL group, patients with leukemic disease more often had absolute lymphocytosis (50% vs. 0%, p = 0.008), thrombocytopenia (60% vs. 11%, p = 0.03), bone marrow involvement (50% vs. 14%, p = 0.04), and CD7 positivity (71% vs. 19%, p = 0.02). Four of five (80%) patients with leukemic ALK-negative ALCL had a complex karyotype, which was significantly higher than that of the patients in the non-leukemic group. A fluorescence in situ hybridization for TP53 was performed on six leukemic ALK-negative ALCL cases and all (100%) had TP53 deletion. There were no significant differences in the other clinicopathologic features, treatment, and complete remission rates between patients in the leukemic versus non-leukemic group (all p > 0.05). The median follow-up of this cohort was 18 months with a range of 0.3–140 months. Eight of nine (90%) patients with leukemic ALK-negative ALCL died, and their overall survival was significantly shorter than that of the patients with non-leukemic disease (median 15.5 vs. 60 months, p = 0.001). In conclusion, we show that the leukemic phase of ALK-negative ALCL is associated with high-risk biologic features and, in particular, a complex karyotype and TP53 deletion. Compared with the non-leukemic ALK-negative ALCL patients, the patients with a leukemic phase of disease have poorer survival and may require more aggressive treatment. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Management of Anaplastic Large Cell Lymphoma)

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17 pages, 4769 KiB

Open AccessArticle

RNA Sequencing of Primary Cutaneous and Breast-Implant Associated Anaplastic Large Cell Lymphomas Reveals Infrequent Fusion Transcripts and Upregulation of PI3K/AKT Signaling via Neurotrophin Pathway Genes

by Arianna Di Napoli, Davide Vacca, Giorgio Bertolazzi, Gianluca Lopez, Maria Piane, Aldo Germani, Evelina Rogges, Giuseppina Pepe, Fabio Santanelli Di Pompeo, Marzia Salgarello, Vaidehi Jobanputra, Susan Hsiao, Kazimierz O. Wrzeszczynski, Emilio Berti and Govind Bhagat

Cancers 2021, 13(24), 6174; https://doi.org/10.3390/cancers13246174 - 7 Dec 2021

Cited by 5 | Viewed by 2970

Abstract

Cutaneous and breast implant-associated anaplastic large-cell lymphomas (cALCLs and BI-ALCLs) are two localized forms of peripheral T-cell lymphomas (PTCLs) that are recognized as distinct entities within the family of ALCL. JAK-STAT signaling is a common feature of all ALCL subtypes, whereas DUSP22/IRF4, TP63 and TYK gene rearrangements have been reported in a proportion of ALK-negative sALCLs and cALCLs. Both cALCLs and BI-ALCLs differ in their gene expression profiles compared to PTCLs; however, a direct comparison of the genomic alterations and transcriptomes of these two entities is lacking. By performing RNA sequencing of 1385 genes (TruSight RNA Pan-Cancer, Illumina) in 12 cALCLs, 10 BI-ALCLs and two anaplastic lymphoma kinase (ALK)-positive sALCLs, we identified the previously reported TYK2-NPM1 fusion in 1 cALCL (1/12, 8%), and four new intrachromosomal gene fusions in 2 BI-ALCLs (2/10, 20%) involving genes on chromosome 1 (EPS15-GNG12 and ARNT-GOLPH3L) and on chromosome 17 (MYO18A-GIT1 and NF1-GOSR1). One of the two BI-ALCL samples showed a complex karyotype, raising the possibility that genomic instability may be responsible for intra-chromosomal fusions in BI-ALCL. Moreover, transcriptional analysis revealed similar upregulation of the PI3K/Akt pathway, associated with enrichment in the expression of neurotrophin signaling genes, which was more conspicuous in BI-ALCL, as well as differences, i.e., over-expression of genes involved in the RNA polymerase II transcription program in BI-ALCL and of the RNA splicing/processing program in cALCL. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Management of Anaplastic Large Cell Lymphoma)

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19 pages, 3964 KiB

Open AccessArticle

Gram-Negative Bacterial Lipopolysaccharide Promotes Tumor Cell Proliferation in Breast Implant-Associated Anaplastic Large-Cell Lymphoma

by Maria Mempin, Honghua Hu, Karen Vickery, Marshall E. Kadin, H. Miles Prince, Nicola Kouttab, John W. Morgan, William P. Adams, Jr. and Anand K. Deva

Cancers 2021, 13(21), 5298; https://doi.org/10.3390/cancers13215298 - 22 Oct 2021

Cited by 8 | Viewed by 2642

Abstract

Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a distinct malignancy associated with textured breast implants. We investigated whether bacteria could trigger the activation and multiplication of BIA-ALCL cells in vitro. BIA-ALCL patient-derived BIA-ALCL tumor cells, BIA-ALCL cell lines, cutaneous ALCL cell lines, an immortal T-cell line (MT-4), and peripheral blood mononuclear cells (PBMC) from BIA-ALCL, capsular contracture, and primary augmentation patients were studied. Cells were subjected to various mitogenic stimulation assays including plant phytohemagglutinin (PHA), Gram-negative bacterial lipopolysaccharide (LPS), Staphylococcal superantigens enterotoxin A (SEA), toxic shock syndrome toxin-1 (TSST-1), or sterilized implant shells. Patient-derived BIA-ALCL tumor cells and BIA-ALCL cell lines showed a unique response to LPS stimulation. This response was dampened significantly in the presence of a Toll-like receptor 4 (TLR4) inhibitor peptide. In contrast, cutaneous ALCL cells, MT-4, and PBMC cells from all patients responded significantly more to PHA, SEA, and TSST-1 than to LPS. Breast implant shells of all surface grades alone did not produce a proliferative response of BIA-ALCL cells, indicating the breast implant does not act as a pro-inflammatory stimulant. These findings indicate a possible novel pathway for LPS to promote BIA-ALCL cell proliferation via a TLR4 receptor-mediated bacterial transformation of T-cells into malignancy. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Management of Anaplastic Large Cell Lymphoma)

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16 pages, 6276 KiB

Open AccessArticle

Constitutive PSGL-1 Correlates with CD30 and TCR Pathways and Represents a Potential Target for Immunotherapy in Anaplastic Large T-Cell Lymphoma

by Beatrice Belmonte, Valeria Cancila, Alessandro Gulino, Mohsen Navari, Walter Arancio, Paolo Macor, Andrea Balduit, Sara Capolla, Gaia Morello, Davide Vacca, Ines Ferrara, Giorgio Bertolazzi, Carmela Rita Balistreri, Paolo Amico, Federica Ferrante, Antonino Maiorana, Tiziana Salviato, Pier Paolo Piccaluga and Alessandro Mangogna

Cancers 2021, 13(12), 2958; https://doi.org/10.3390/cancers13122958 - 12 Jun 2021

Cited by 3 | Viewed by 3265

Abstract

Due to the high expression of P-selectin glycoprotein ligand-1 (PSGL-1) in lymphoproliferative disorders and in multiple myeloma, it has been considered as a potential target for humoral immunotherapy, as well as an immune checkpoint inhibitor in T-cells. By investigating the expression of SELPLG in 678 T- and B-cell samples by gene expression profiling (GEP), further supported by tissue microarray and immunohistochemical analysis, we identified anaplastic large T-cell lymphoma (ALCL) as constitutively expressing SELPLG at high levels. Moreover, GEP analysis in CD30+ ALCLs highlighted a positive correlation of SELPLG with TNFRSF8 (CD30-coding gene) and T-cell receptor (TCR)-signaling genes (LCK, LAT, SYK and JUN), suggesting that the common dysregulation of TCR expression in ALCLs may be bypassed by the involvement of PSGL-1 in T-cell activation and survival. Finally, we evaluated the effects elicited by in vitro treatment with two anti-PSGL-1 antibodies (KPL-1 and TB5) on the activation of the complement system and induction of apoptosis in human ALCL cell lines. In conclusion, our data demonstrated that PSGL-1 is specifically enriched in ALCLs, altering cell motility and viability due to its involvement in CD30 and TCR signaling, and it might be considered as a promising candidate for novel immunotherapeutic approaches in ALCLs. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Management of Anaplastic Large Cell Lymphoma)

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41 pages, 15241 KiB

Open AccessReview

ALK-Negative Anaplastic Large Cell Lymphoma: Current Concepts and Molecular Pathogenesis of a Heterogeneous Group of Large T-Cell Lymphomas

by Sergio Pina-Oviedo, Carlos Ortiz-Hidalgo, Adrian Alejandro Carballo-Zarate and Alejandra Zarate-Osorno

Cancers 2021, 13(18), 4667; https://doi.org/10.3390/cancers13184667 - 17 Sep 2021

Cited by 19 | Viewed by 7624

Abstract

Anaplastic large cell lymphoma (ALCL) is a subtype of CD30+ large T-cell lymphoma (TCL) that comprises ~2% of all adult non-Hodgkin lymphomas. Based on the presence/absence of the rearrangement and expression of anaplastic lymphoma kinase (ALK), ALCL is divided into ALK+ and ALK-, and both differ clinically and prognostically. This review focuses on the historical points, clinical features, histopathology, differential diagnosis, and relevant cytogenetic and molecular alterations of ALK- ALCL and its subtypes: systemic, primary cutaneous (pc-ALCL), and breast implant-associated (BIA-ALCL). Recent studies have identified recurrent genetic alterations in this TCL. In systemic ALK- ALCL, rearrangements in DUSP22 and TP63 are detected in 30% and 8% of cases, respectively, while the remaining cases are negative for these rearrangements. A similar distribution of these rearrangements is seen in pc-ALCL, whereas none have been detected in BIA-ALCL. Additionally, systemic ALK- ALCL—apart from DUSP22-rearranged cases—harbors JAK1 and/or STAT3 mutations that result in the activation of the JAK/STAT signaling pathway. The JAK1/3 and STAT3 mutations have also been identified in BIA-ALCL but not in pc-ALCL. Although the pathogenesis of these alterations is not fully understood, most of them have prognostic value and open the door to the use of potential targeted therapies for this subtype of TCL. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Management of Anaplastic Large Cell Lymphoma)

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9 pages, 843 KiB

Open AccessCommentary

An Update on the Current Genomic Landscape of Breast Implant-Associated Anaplastic Large Cell Lymphoma

by Sean Harrop, Neha Mehta-Shah, Criselle Dsouza, Ella Thompson, Anand Deva and Henry Miles Prince

Cancers 2021, 13(19), 4921; https://doi.org/10.3390/cancers13194921 - 30 Sep 2021

Cited by 1 | Viewed by 2270

Abstract

Breast implant-associated lymphoma (BIA-ALCL) is a rare subtype of anaplastic large-cell lymphoma associated with breast prostheses. Most patients present with a localised periprosthetic effusion and are managed with removal of the implant and surrounding capsule. Less commonly, the lymphoma can form a mass associated with the capsule and rarely can present with disseminated disease. Recent series characterising the genomic landscape of BIA-ALCL have led to insights into the mechanisms of lymphomagenesis. Constitutive JAK/STAT pathway activation has emerged as a likely key component while, more recently, aberrancies in epigenetic regulators have been reported. This review describes the genomic characterisation reported to date and the insight these findings have provided into this rare entity. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Management of Anaplastic Large Cell Lymphoma)

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15 pages, 864 KiB

Open AccessSystematic Review

Clinical Features and Prognostic Factors for Primary Anaplastic Large Cell Lymphoma of the Central Nervous System: A Systematic Review

by Yudai Hirano, Satoru Miyawaki, Shota Tanaka, Kazuki Taoka, Hiroki Hongo, Yu Teranishi, Hirokazu Takami, Shunsaku Takayanagi, Mineo Kurokawa and Nobuhito Saito

Cancers 2021, 13(17), 4358; https://doi.org/10.3390/cancers13174358 - 28 Aug 2021

Cited by 8 | Viewed by 2634

Abstract

Primary anaplastic large cell lymphoma (ALCL) of the central nervous system (CNS) is a subtype of primary CNS lymphoma (PCNSL). There are very few comprehensive reports on this extremely rare tumor. Therefore, it is necessary to investigate the clinical features and prognostic factors for primary ALCL of the CNS. We performed a systematic review of the published literature. Past cases were comprehensively searched using PubMed, Cochrane Library, and Web of Science. Clinical information, such as age, sex, anaplastic lymphoma kinase (ALK) status, lesion sites, treatment methods, and survivorship were extracted. Thirty-nine cases with information on ALK status and treatment course were identified. The average observation period was 13 months, and the overall 2-year survival rate was 58%. Univariate analyses showed a statistically significantly better prognosis among patients < 40 years of age (p = 0.039, HR 0.32 (0.11–0.95)) and in relation to ALK positivity (p = 0.010, HR 0.24 (0.08–0.71) and methotrexate treatment (p = 0.003, HR 0.17 (0.05–0.56)). Because of the sparsity of cases, it is necessary to accumulate cases in order to perform more detailed analyses. Full article

(This article belongs to the Special Issue Molecular Pathogenesis and Management of Anaplastic Large Cell Lymphoma)

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