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Simple Summary: It is challenging for pathologists to diagnose primary gastrointestinal T-cell neoplasms. Besides the rarity of the diseases, the small biopsy material makes it more difficult to differentiate between non-neoplastic inflammation and secondary involvement of extra gastrointestinal lymphoma. Since this group of diseases ranges from aggressive ones with a very poor prognosis to indolent ones that require caution to avoid overtreatment, the impact of the diagnosis on the patient is enormous. Although early treatment of aggressive lymphoma is essential, the treatment strategy is not well established, which is a problem for clinicians. This review provides a cross-sectional comparison of histological findings. Unlike previous reviews, we summarized up-to-date clinically relevant information including the treatment strategies as well as practical differential diagnosis based on thorough literature review. Abstract: Primary gastrointestinal (GI) T-cell neoplasms are extremely rare heterogeneous disease entities with distinct clinicopathologic features. Given the different prognoses of various disease subtypes, clinicians and pathologists must be aware of the key characteristics of these neoplasms, despite their rarity. The two most common aggressive primary GI T-cell lymphomas are enteropathy-associated T-cell lymphoma and monomorphic epitheliotropic intestinal T-cell lymphoma. In addition, extranodal natural killer (NK)/T-cell lymphoma of the nasal type and anaplastic large cell lymphoma may also occur in the GI tract or involve it secondarily. In the revised 4th World Health Organization classification, indolent T-cell lymphoproliferative disorder of the GI tract has been incorporated as a provisional entity. In this review, we summarize up-to-date clinicopathological features of these disease entities, including the molecular characteristics of primary GI T-cell lymphomas and indolent lymphoproliferative disorders. We focus on the latest treatment approaches, which have not been summarized in existing reviews. Further, we provide a comprehensive review of available literature to address the following questions: How can pathologists discriminate subtypes with different clinical prognoses? How can primary GI neoplasms be distinguished from secondary involvement? How can these neoplasms be distinguished from non-specific inflammatory changes at an early stage?

Simple Summary The development of a rare cancer of the immune system (lymphoma) associated with breast implants has been increasingly reported around the world. It has been hypothesized that the cancer is triggered by inflammation from bacteria residing within the textured surface of these implants, transforming the lymphocytes of some genetically prone patients over many years. This study shows that bacteria rather than the implant itself can trigger activation and multiplication of these cancer cells in the laboratory, lending support that bacteria and their products play an important role in causation. The unique response of these cancer cells to bacterial antigen was dampened significantly in the presence of a Toll-like receptor 4 inhibitor peptide. This finding has significance for both cancer prevention and treatment. 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.

In 50–60% of cases, systemic anaplastic large cell lymphoma (ALCL) is characterized by the t(2, 5)(p23, q35) or one of its variants, considered to be causative for anaplastic lymphoma kinase (ALK)-positive (ALK+) ALCL. Key pathogenic events in ALK-negative (ALK−) ALCL are less well defined. We have previously shown that deregulation of oncogenic genes surrounding the chromosomal breakpoints on 2p and 5q is a unifying feature of both ALK+ and ALK− ALCL and predisposes for occurrence of t(2, 5). Here, we report that the invariant chain of the MHC-II complex CD74 or li, which is encoded on 5q32, can act as signaling molecule, and whose expression in lymphoid cells is usually restricted to B cells, is aberrantly expressed in T cell-derived ALCL. Accordingly, ALCL shows an altered DNA methylation pattern of the CD74 locus compared to benign T cells. Functionally, CD74 ligation induces cell death of ALCL cells. Furthermore, CD74 engagement enhances the cytotoxic effects of conventional chemotherapeutics in ALCL cell lines, as well as the action of the ALK-inhibitor crizotinib in ALK+ ALCL or of CD95 death-receptor signaling in ALK− ALCL. Additionally, a subset of ALCL cases expresses the proto-oncogene MET, which can form signaling complexes together with CD74. Finally, we demonstrate that the CD74-targeting antibody-drug conjugate STRO-001 efficiently and specifically kills CD74-positive ALCL cell lines in vitro. Taken together, these findings enabled us to demonstrate aberrant CD74-expression in ALCL cells, which might serve as tool for the development of new treatment strategies for this lymphoma entity.

Simple Summary Despite success of targeted therapy, cancer cells very often find a way to survive treatment; this eventually causes a tumor to relapse. In a particular type of lymphoma carrying a specific chromosomal rearrangement named anaplastic large-cell lymphoma (ALCL), selective drugs targeting the cause of the disease can induce spectacular remission of chemotherapy-resistant cancer. However, the lymphoma relapses again in about half of the cases, leaving no therapeutic options. We studied the possibility to combine two simultaneous treatments in order to prevent the relapse, starting from the hypothesis that acquiring resistance to two drugs at the same time is statistically very unlikely. We demonstrate that treating lymphoma cells with drug combinations has superior efficacy in comparison with single drug treatments, both in cell cultures and in mice. Abstract 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.

Simple Summary ALK- anaplastic large cell lymphoma (ALK- ALCL) is a rare subtype of CD30+ large T-cell lymphoma that typically affects older adults and has a poor prognosis. Recognition of its histopathologic spectrum, subtypes, and of other tumors that can resemble ALK- ALCL is crucial to avoid making a wrong diagnosis that could result in inappropriate treatment for a patient. In recent years, several important studies have identified recurrent molecular alterations that have shed light on the pathogenesis of this lymphoma. However, on the other hand, putting all this vast information together into a concise form has become challenging. In this review, we present not only a more detailed view of the histopathologic findings of ALK- ALCL but also, we attempt to provide a more simplified perspective of the relevant genetic and molecular alterations of this type of lymphoma, that in our opinion, is not available to date. 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.

Simple Summary Breast implant-associated lymphoma is a unique entity that arises in the setting of breast prostheses due to a complex interplay of external and internal factors. Understanding of the mechanisms of pathogenesis is yet to be fully elucidated but recurrent mutations in signalling pathways, tumour suppressors and epigenetic regulators have been reported. This article summarises the key studies to date that have described these genetic aberrancies, which have provided an insight into potential pathways to lymphogenesis. 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.

Simple Summary This review summarizes the main features of anaplastic large cell lymphoma (ALCL) subtypes focusing on activated biological pathways that may have clinical significance for diagnosis, prognosis and personalized therapy. Abstract ALCL is a tumor of activated T cells and possibly innate lymphoid cells with several subtypes according to clinical presentation and genetic lesions. On one hand, the expression of transcription factors and cytokine receptors triggers signaling pathways. On the other hand, ALCL tumor cells also produce many proteins including chemokines, cytokines and growth factors that affect patient symptoms. Examples are accumulation of granulocytes stimulated by IL-8, IL-17, IL-9 and IL-13; epidermal hyperplasia and psoriasis-like skin lesions due to IL-22; and fever and weight loss in response to IL-6 and IFN-γ. In this review, we focus on the biology of the main ALCL subtypes as the identification of signaling pathways and ALCL-derived cytokines offers opportunities for targeted therapies.

Primary gastrointestinal T/NK cell lymphoma (GI-TNKL) is an uncommon and heterogeneous group of lymphoid malignancies. We aimed to investigate their subtype distribution, clinicopathologic characteristics, and clinical outcomes. A total of 38 GI-TNKL cases and their clinical and pathological characteristics were analyzed. GI-TNKL occurred in adults with a median patient age in the sixth decade of life and showed a slight male predominance. The most common histologic type was extranodal NK/T-cell lymphoma, nasal type (ENKTL, 34.2%), followed by monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL, 31.6%), intestinal T-cell lymphoma, NOS (ITCL, NOS, 18.4%), anaplastic large cell lymphoma, ALK-negative (ALCL, ALK, 13.2%). The small intestine was the primary affected region. More than 90% of patients complained of various GI symptoms and cases with advanced Lugano stage, high IPI score, or bowel perforation that required emergent operation were not uncommon. GI-TNKL also showed aggressive behavior with short progression-free survival and overall survival. This thorough clinical and pathological descriptive analysis will be helpful for accurate understanding, diagnosis, and treatment.

Simple Summary Autophagy is a cell survival and recycling mechanism which protects cancer cells upon therapeutic drug treatment. Here we investigated the impact of autophagy inhibition in a cancer of lymphoid origin, namely ALK-positive anaplastic large cell lymphoma (ALK + ALCL). We inhibited autophagy in two distinct cell subsets of ALK + ALCL, one of which we previously shown to possess more stem-like and tumorigenic properties. Our study found that blockage of autophagy in the stem-like subset resulted in marked drug-sensitization to crizotinib, a current therapeutic agent used to treat ALK + ALCL. We also found differential involvement of the Myconcogene in the autophagy process within the two subsets and identified its relative importance to the stem-like population. Our research suggests inhibition of autophagy alongside crizotinib preferentially targets stem-like cells, thus improving crizotinib therapy. Abstract Previously it was shown that autophagy contributes to crizotinib resistance in ALK-positive anaplastic large cell lymphoma (ALK + ALCL). We asked if autophagy is equally important in two distinct subsets of ALK + ALCL, namely Reporter Unresponsive (RU) and Reporter Responsive (RR), of which RR cells display stem-like properties. Autophagic flux was assessed with a fluorescence tagged LC3 reporter and immunoblots to detect endogenous LC3 alongside chloroquine, an autophagy inhibitor. The stem-like RR cells displayed significantly higher autophagic response upon crizotinib treatment. Their exaggerated autophagic response is cytoprotective against crizotinib, as inhibition of autophagy using chloroquine or shRNA against BECN1 or ATG7 led to a decrease in their viability. In contrast, autophagy inhibition in RU resulted in minimal changes. Since the differential protein expression of MYC is a regulator of the RU/RR dichotomy and is higher in RR cells, we asked if MYC regulates the autophagy-mediated cytoprotective effect. Inhibition of MYC in RR cells using shRNA significantly blunted crizotinib-induced autophagic response and effectively suppressed this cytoprotective effect. In conclusion, stem-like RR cells respond with rapid and intense autophagic flux which manifests with crizotinib resistance. For the first time, we have highlighted the direct role of MYC in regulating autophagy and its associated chemoresistance phenotype in ALK + ALCL stem-like cells.

Simple Summary Anaplastic lymphoma kinase (ALK) is a tyrosine kinase associated with Anaplastic Large Cell lymphoma (ALCL) through oncogenic translocations mainly NPM-ALK. Chemotherapy is effective in ALK(+) ALCL patients and induces remission rates of approximately 80%. The remaining patients do not respond to chemotherapy and some patients have drug-resistant relapses. Different classes of ALK tyrosine kinase inhibitors (TKI) are available but used exclusively for EML4-ALK (+) lung cancers. The significant toxicities of most ALK inhibitors explain the delay in their use in pediatric ALCL patients. Some ALCL patients do not respond to the first generation TKI or develop an acquired resistance. Combination therapy with ALK inhibitors in ALCL is the current challenge. Abstract Initially discovered in anaplastic large cell lymphoma (ALCL), the ALK anaplastic lymphoma kinase is a tyrosine kinase which is affected in lymphomas by oncogenic translocations, mainly NPM-ALK. To date, chemotherapy remains a viable option in ALCL patients with ALK translocations as it leads to remission rates of approximately 80%. However, the remaining patients do not respond to chemotherapy and some patients have drug-resistant relapses. It is therefore crucial to identify new and better treatment options. Nowadays, different classes of ALK tyrosine kinase inhibitors (TKI) are available and used exclusively for EML4-ALK (+) lung cancers. In fact, the significant toxicities of most ALK inhibitors explain the delay in their use in ALCL patients, who are predominantly children. Moreover, some ALCL patients do not respond to Crizotinib, the first generation TKI, or develop an acquired resistance months following an initial response. Combination therapy with ALK inhibitors in ALCL is the current challenge.

Simple Summary Although chemotherapy is associated with high relapse rates and numerous side effects, it is still used as the front line treatment of anaplastic large cell lymphoma (ALCL). Therefore, alternative treatment options for ALCL are needed. In this study, we show that B7-H3 is a novel and promising target in ALCLs, and demonstrate that B7-H3 directed chimeric antigen receptor (CAR) T cells have therapeutic potency in controlling ALCL tumor growth. Abstract Potent CAR-T therapies that target appropriate antigens can benefit the treatment of anaplastic lymphoma kinase-positive (ALK+) anaplastic large cell lymphoma (ALCL), which is the most common subtype of T cell lymphoma. In this study, we observed overexpression of B7-H3 in ALCL cell lines derived from clinical samples and differential expression of B7-H3 in an ALK-induced T cell transformation model. A B7-H3-redirected CAR based on scFv from mAb 376.96 was developed. B7-H3 CAR-T cells showed strong cytotoxicity and cytokine secretion against target ALCL cells (SUP-M2, SU-DHL-1, and Karpas 299) in vitro. Furthermore, the B7-H3 CAR-T cells exhibited proliferative capacity and a memory phenotype upon repeated antigen stimulation. We demonstrated that B7-H3 CAR-T cells could promptly eradicate ALCL in murine xenografts. Taken together, B7-H3 is a novel and promising target in ALCLs and B7-H3 CAR-T may be a viable treatment option for ALCL.

Breast implant-associated lymphoma (BIA-ALCL) has recently been recognized as an independent peripheral T-cell lymphoma (PTCL) entity. In this study, we generated the first BIA-ALCL patient-derived tumor xenograft (PDTX) model (IL89) and a matching continuous cell line (IL89_CL#3488) to discover potential vulnerabilities and druggable targets. We characterized IL89 and IL89_CL#3488, both phenotypically and genotypically, and demonstrated that they closely resemble the matching human primary lymphoma. The tumor content underwent significant enrichment along passages, as confirmed by the increased variant allele frequency (VAF) of mutations. Known aberrations (JAK1 and KMT2C) were identified, together with novel hits, including PDGFB, PDGFRA, and SETBP1. A deep sequencing approach allowed the detection of mutations below the Whole Exome Sequencing (WES) sensitivity threshold, including JAK1G1097D, in the primary sample. RNA sequencing confirmed the expression of a signature of differentially expressed genes in BIA-ALCL. Next, we tested IL89&rsquo, s sensitivity to the JAK inhibitor ruxolitinib and observed a potent anti-tumor effect, both in vitro and in vivo. We also implemented a high-throughput drug screening approach to identify compounds associated with increased responses in the presence of ruxolitinib. In conclusion, these new IL89 BIA-ALCL models closely recapitulate the primary correspondent lymphoma and represent an informative platform for dissecting the molecular features of BIA-ALCL and performing pre-clinical drug discovery studies, fostering the development of new precision medicine approaches.

Anaplastic large cell lymphoma (ALCL) is the most common T-cell lymphoma in children. ALCL cells characteristically express surface CD30 molecules and carry the pathogenic ALK oncogene, both of which are diagnostic biomarkers and are also potential therapeutic targets. For precision therapy, we report herein a protamine nanomedicine incorporated with oligonucleotide aptamers to selectively target lymphoma cells, a dsDNA/drug payload to efficiently kill targeted cells, and an siRNA to specifically silence ALK oncogenes. The aptamer-equipped protamine nanomedicine was simply fabricated through a non-covalent charge-force reaction. The products had uniform structure morphology under an electron microscope and a peak diameter of 103 nm by dynamic light scattering measurement. Additionally, flow cytometry analysis demonstrated that under CD30 aptamer guidance, the protamine nanomedicine specifically bound to lymphoma cells, but did not react to off-target cells in control experiments. Moreover, specific cell targeting and intracellular delivery of the nanomedicine were also validated by electron and confocal microscopy. Finally, functional studies demonstrated that, through combined cell-selective chemotherapy using a drug payload and oncogene-specific gene therapy using an siRNA, the protamine nanomedicine effectively killed lymphoma cells with little toxicity to off-target cells, indicating its potential for precision therapy.

Simple Summary Primary anaplastic large cell lymphoma (ALCL) of the central nervous system (CNS) is a subtype of primary central nervous system lymphoma (PCNSL). ALCL is divided into anaplastic lymphoma kinase (ALK)-positive ALCL and ALK-negative ALCL, according to ALK expression. ALK-positive cancers tend to develop at a younger age and tend to have a better prognosis. Almost all past articles on primary ALCL of the CNS have been case reports and there have been no randomized trials or cohort studies on this subject. We thus performed a systematic review of primary ALCL of the CNS. According to the author’s survey, 36 case reports have been published in English-language journals. In this paper, we have summarized the clinical features and prognostic factors for primary ALCL of the CNS based on previous studies. 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.

Simple Summary Minimal residual disease (MRD) describes the detection of a few remaining malignant cells in blood or bone marrow with molecular methods or flow cytometry. The detection of MRD in patients with leukemia during therapy indicates the risk of relapse. Its use for treatment stratification is state of the art in all modern leukemia treatment protocols. In pediatric non-Hodgkin lymphoma patients, minimal amounts of tumor cells, so-called minimal disseminated disease (MDD), can often be detected in blood or bone marrow at diagnosis. In children with ALK-positive anaplastic large cell lymphoma, MDD and MRD detected in the blood or bone marrow is associated with high relapse risk. For patients with Burkitt lymphoma or -leukemia or lymphoblastic lymphoma, the meaning of MDD and MRD is less clear. This review summarizes the current knowledge, techniques, application, and challenges in minimal disease detection in pediatric non-Hodgkin lymphoma. Abstract Minimal residual disease (MRD) detection is established routine practice for treatment stratification in leukemia and used for treatment optimization in adult lymphomas. Minimal disease studies in childhood non-Hodgkin lymphomas are challenged by stratified treatment in different subtypes, high cure rates, low patient numbers, limited initial tumor material, and early progression. Current clinical applications differ between the subtypes. A prognostic value of minimal disseminated disease (MDD) could not yet be clearly established for lymphoblastic lymphoma using flow cytometry and PCR-based methods for T-cell receptor (TCR) or immunoglobulin (IG) rearrangements. MYC–IGH fusion sequences or IG rearrangements enable minimal disease detection in Burkitt lymphoma and -leukemia. An additional prognostic value of MDD in Burkitt lymphoma and early MRD in Burkitt leukemia is implicated by single studies with risk-adapted therapy. MDD and MRD determined by PCR for ALK-fusion transcripts are independent prognostic parameters for patients with ALK-positive anaplastic large cell lymphoma (ALCL). They are introduced in routine clinical practice and used for patient stratification in clinical studies. Early MRD might serve as an endpoint for clinical trials and for guiding individual therapy. Validation of MDD and MRD as prognostic parameters is required for all subtypes but ALCL. Next-generation sequencing-based methods may provide new options and applications for minimal disease evaluation in childhood lymphomas.

Forkhead Box M1 (FOXM1) is an oncogenic transcription factor implicated in the pathogenesis of solid and hematologic cancers. In this study, we examined the significance of FOXM1 in NPM-ALK-positive anaplastic large cell lymphoma (NPM-ALK + ALCL), with a focus on how it interacts with NPM-ALK, which is a key oncogenic driver in these tumors. FOXM1 was expressed in NPM-ALK + ALCL cell lines (5/5), patient samples (21/21), and tumors arising in NPM-ALK transgenic mice (4/4). FOXM1 was localized in the nuclei and confirmed to be transcriptionally active. Inhibition of FOXM1 in two NPM-ALK + ALCL cells using shRNA and pharmalogic agent (thiostrepton) resulted in reductions in cell growth and soft-agar colony formation, which were associated with apoptosis and cell-cycle arrest. FOXM1 is functionally linked to NPM-ALK, as FOXM1 enhanced phosphorylation of the NPM-ALK/STAT3 axis. Conversely, DNA binding and transcriptional activity of FOXM1 was dependent on the expression of NPM-ALK. Further studies showed that this dependency hinges on the binding of FOXM1 to NPM1 that heterodimerizes with NPM-ALK, and the phosphorylation status of NPM-ALK. In conclusion, we identified FOXM1 as an important oncogenic protein in NPM-ALK+ ALCL. Our results exemplified that NPM-ALK exerts oncogenic effects in the nuclei and illustrated a novel role of NPM1 in NPM-ALK pathobiology.

ALK is a receptor tyrosine kinase, associated with many tumor types as diverse as anaplastic large cell lymphomas, inflammatory myofibroblastic tumors, breast and renal cell carcinomas, non-small cell lung cancer, neuroblastomas, and more. This makes ALK an attractive target for cancer therapy. Since ALK–driven tumors are dependent for their proliferation on the constitutively activated ALK kinase, a number of tyrosine kinase inhibitors have been developed to block tumor growth. While some inhibitors are under investigation in clinical trials, others are now approved for treatment, notably in ALK-positive lung cancer. Their efficacy is remarkable, however limited in time, as the tumors escape and become resistant to the treatment through different mechanisms. Hence, there is a pressing need to target ALK-dependent tumors by other therapeutic strategies, and possibly use them in combination with kinase inhibitors. In this review we will focus on the therapeutic potential of proapoptotic ALK-derived peptides based on the dependence receptor properties of ALK. We will also try to make a non-exhaustive list of several alternative treatments targeting ALK-dependent and independent signaling pathways.

With the aim of describing the long-term follow-up and to define the prognostic role of the clinical/pathological/molecular characteristics at diagnosis for childhood, adolescent and young adults affected by anaplastic large cell lymphoma (ALCL), we analyzed 420 patients aged up to 22 years homogeneously treated within the international ALCL99 trial. The 10-year progression free survival (PFS) was 70% and overall survival was 90%, rare late relapses occurred but no secondary malignancies were reported. Among clinical/pathological characteristics, only patients presenting a small cell/lymphohistiocytic (SC/LH) pattern were independently associated with risk of failure (hazard ratio = 2.49). Analysis of minimal disseminated disease (MDD), available for 162 patients, showed that both SC/LH pattern (hazard ratio = 2.4) and MDD positivity (hazard ratio = 2.15) were significantly associated with risk of failure in multivariate analysis. Considering MDD and SC/LH results, patients were separated into three biological/pathological (bp) risk groups: a high-risk group (bpHR) including MDD-positive patients with SC/LH pattern, a low-risk group (bpLR) including MDD-negative patients without SC/LH pattern, and an intermediate-risk group (bpIR) including remaining patients. The 10-year PFS was 40%, 75% and 86% for bpHR, bpIR and bpLR, respectively (p &lt, 0.0001). These results should be considered in the design of future ALCL trials to tailor individual treatments.

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.

Patients with anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) mount a humoral and cellular immune response against ALK. More than 90% of children and adolescents with ALK-positive ALCL have detectable anti-ALK antibodies in serum or plasma, and the antibody titer inversely correlates with the risk of relapse. ALK-specific CD8 and CD4 T cell responses have been described in patients with ALK-positive ALCL. Vaccination with ALK DNA led to protection against lymphoma growth in a murine model. Collectively, these data suggest that the ALK-specific immune response is involved in the control of the disease. The characteristics of the humoral and cellular immune response against ALK as well as tumor immune escape mechanisms have been increasingly investigated. However, tumor and host factors contributing to the individual immune response against ALK are still largely unknown. Depending on the individual strength of the immune response and its determinants, individualized immunological approaches might be appropriate for the consolidation of ALCL patients. Strategies such as ALK vaccination could be effective for those with a pre-existing anti-tumor immunity, while an allogeneic blood stem cell transplantation or check-point inhibition could be effective for others.

The Activator Protein-1 (AP-1) transcription factor (TF) family, composed of a variety of members including c-JUN, c-FOS and ATF, is involved in mediating many biological processes such as proliferation, differentiation and cell death. Since their discovery, the role of AP-1 TFs in cancer development has been extensively analysed. Multiple in vitro and in vivo studies have highlighted the complexity of these TFs, mainly due to their cell-type specific homo- or hetero-dimerization resulting in diverse transcriptional response profiles. However, as a result of the increasing knowledge of the role of AP-1 TFs in disease, these TFs are being recognized as promising therapeutic targets for various malignancies. In this review, we focus on the impact of deregulated expression of AP-1 TFs in CD30-positive lymphomas including Classical Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma.

Anaplastic Lymphoma Kinase (ALK)-positive Anaplastic Large Cell Lymphoma (ALCL), remains one of the most curable cancers in the paediatric setting; multi-agent chemotherapy cures approximately 65-90% of patients. Over the last two decades, major efforts have focused on improving the survival rate by intensification of combination chemotherapy regimens and employing stem cell transplantation for chemotherapy-resistant patients. More recently, several new and 'renewed' agents have offered the opportunity for a change in the paradigm for the management of both chemo-sensitive and chemo-resistant forms of ALCL. The development of ALK inhibitors following the identification of the EML4-ALK fusion gene in Non-Small Cell Lung Cancer (NSCLC) has opened new possibilities for ALK-positive ALCL. The uniform expression of CD30 on the cell surface of ALCL has given the opportunity for anti-CD30 antibody therapy. The re-evaluation of vinblastine, which has shown remarkable activity as a single agent even in the face of relapsed disease, has led to the consideration of a revised approach to frontline therapy. The advent of immune therapies such as checkpoint inhibition has provided another option for the treatment of ALCL. In fact, the number of potential new agents now presents a real challenge to the clinical community that must prioritise those thought to offer the most promise for the future. In this review, we will focus on the current status of paediatric ALCL therapy, explore how new and 'renewed' agents are re-shaping the therapeutic landscape for ALCL, and identify the strategies being employed in the next generation of clinical trials.

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.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that has been implicated in the pathogenesis of a variety of neoplasms. As suggested by its name, ALK was first described as part of a translocation product in cases of anaplastic large-cell lymphoma, with other genetic and cytogenetic ALK mutations subsequently coming to attention in the development of many other hematologic and solid organ malignancies. ALK has now been shown to play a role in the pathogenesis of several cutaneous malignancies, including secondary cutaneous systemic anaplastic large-cell lymphoma (ALCL) and primary cutaneous ALCL, melanoma, spitzoid tumors, epithelioid fibrous histiocytoma, Merkel cell carcinoma, and basal cell carcinoma. The characterization of ALK-positivity in these cutaneous malignancies presents exciting opportunities for utilizing ALK-targeted inhibitors in the treatment of these diseases.

Targeted therapy is an effective, rational, and safe approach to solid and hematological tumors treatment. Unfortunately, a significant fraction of patients treated with tyrosine kinase inhibitors (TKI) relapses mainly because of gene amplification, mutations, or other bypass mechanisms. Recently a growing number of papers showed how, in some cases, resistance due to oncogene overexpression may be associated with drug addiction: cells able to proliferate in the presence of high TKI doses become also TKI dependent, undergoing cellular stress, and apoptosis/death upon drug withdrawal. Notably, if a sub-cellular population survives TKI discontinuation it is also partially re-sensitized to the same drug. Thus, it is possible that a subset of patients relapsing upon TKI treatment may benefit from a discontinuous therapeutic schedule. We focused on two different hematologic malignancies, chronic myeloid leukemia (CML) and anaplastic large cell lymphoma (ALCL), both successfully treatable with TKIs. The two models utilized (LAMA and SUP-M2) differed in having oncogene overexpression as the sole cause of drug resistance (CML), or additionally carrying kinase domain mutations (ALCL). In both cases drug withdrawal caused a sudden overload of oncogenic signal, enhanced mitochondria activity, induced the release of a high amount of reactive oxygen species (ROS), and caused genotoxic stress and massive cell death. In LAMA cells (CML) we could rescue the cells from death by partially blocking downstream oncogenic signaling or lowering ROS detrimental effect by adding reduced glutathione.

T-cell non-Hodgkin lymphoma is a heterogeneous disease ranging from malignancies arising from thymic T cells halted in development, through to mature, circulating peripheral T cells. The latter cases are diagnostically problematic with many entering the category of peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS). Anaplastic large cell lymphoma (ALCL) is one of the exceptions to this whereby aberrant expression of anaplastic lymphoma kinase (ALK) and the distinctive presence of cell surface CD30 places this entity in its own class. Besides the expression of a well-studied oncogenic translocation, ALCL, ALK+ may also have a unique pathogenesis with a thymic origin like T lymphoblastic lymphoma but a peripheral presentation akin to PTCL. This perspective discusses evidence towards the potential origin of ALCL, ALK+, and mechanisms that may give rise to its unique phenotype.

Anaplastic lymphoma kinase positive anaplastic large cell lymphomas (ALK+ ALCL) are an aggressive pediatric disease. The therapeutic options comprise chemotherapy, which is efficient in approximately 70% of patients, and targeted therapies, such as crizotinib (an ALK tyrosine kinase inhibitor (TKI)), used in refractory/relapsed cases. Research efforts have also converged toward the development of combined therapies to improve treatment. In this context, we studied whether autophagy could be modulated to improve crizotinib therapy. Autophagy is a vesicular recycling pathway, known to be associated with either cell survival or cell death depending on the cancer and therapy. We previously demonstrated that crizotinib induced cytoprotective autophagy in ALK+ lymphoma cells and that its further intensification was associated with cell death. In line with these results, we show here that combined ALK and Rapidly Accelerated Fibrosarcoma 1 (RAF1) inhibition, using pharmacological (vemurafenib) or molecular (small interfering RNA targeting RAF1 (siRAF1) or microRNA-7-5p (miR-7-5p) mimics) strategies, also triggered autophagy and potentiated the toxicity of TKI. Mechanistically, we found that this combined therapy resulted in the decrease of the inhibitory phosphorylation on Unc-51-like kinase-1 (ULK1) (a key protein in autophagy initiation), which may account for the enforced autophagy and cytokilling effect. Altogether, our results support the development of ALK and RAF1 combined inhibition as a new therapeutic approach in ALK+ ALCL.

Anaplastic large cell lymphoma (ALCL) and classical Hodgkin lymphoma (cHL) are lymphomas that contain CD30-expressing tumor cells and have numerous pathological similarities. Whereas ALCL is usually diagnosed at an advanced stage, cHL more frequently presents with localized disease. The aim of the present study was to elucidate the mechanisms underlying the different clinical presentation of ALCL and cHL. Chemokine and chemokine receptor expression were similar in primary ALCL and cHL cases apart from the known overexpression of the chemokines CCL17 and CCL22 in the Hodgkin and Reed-Sternberg (HRS) cells of cHL. Consistent with the overexpression of these chemokines, primary cHL cases encountered a significantly denser T cell microenvironment than ALCL. Additionally to differences in the interaction with their microenvironment, cHL cell lines presented a lower and less efficient intrinsic cell motility than ALCL cell lines, as assessed by time-lapse microscopy in a collagen gel and transwell migration assays. We thus propose that the combination of impaired basal cell motility and differences in the interaction with the microenvironment hamper the dissemination of HRS cells in cHL when compared with the tumor cells of ALCL.

Autophagy is an evolutionarily conserved catabolic process, which is used by the cells for cytoplasmic quality control. This process is induced following different kinds of stresses e.g., metabolic, environmental, or therapeutic, and acts, in this framework, as a cell survival mechanism. However, under certain circumstances, autophagy has been associated with cell death. This duality has been extensively reported in solid and hematological cancers, and has been observed during both tumor development and cancer therapy. As autophagy plays a critical role at the crossroads between cell survival and cell death, its involvement and therapeutic modulation (either activation or inhibition) are currently intensively studied in cancer biology, to improve treatments and patient outcomes. Over the last few years, studies have demonstrated the occurrence of autophagy in different Anaplastic Lymphoma Kinase (ALK)-associated cancers, notably ALK-positive anaplastic large cell lymphoma (ALCL), non-small cell lung carcinoma (NSCLC), Neuroblastoma (NB), and Rhabdomyosarcoma (RMS). In this review, we will first briefly describe the autophagic process and how it can lead to opposite outcomes in anti-cancer therapies, and we will then focus on what is currently known regarding autophagy in ALK-associated cancers.

Genomic stability is crucial for cell life and transmitting genetic material is one of the primary tasks of the cell. The cell needs to be able to recognize any possible error and quickly repair it, and thus, cells have developed several mechanisms to detect DNA damage and promote repair during evolution. The DNA damage response (DDR) and DNA repair pathways ensure the control of possible errors that could impair the duplication of genetic information and introduce variants in the DNA. Endogenous and exogenous factors compromise genomic stability and cause dysregulation in the DDR and DNA repair pathways. Cancer cells often impair these mechanisms to overcome cellular barriers (cellular senescence and/or apoptosis), leading to malignancy. NPM (nucleophosmin)-ALK (anaplastic lymphoma kinase) is an oncogenic tyrosine kinase that is involved in the development of anaplastic large cell lymphoma (ALCL). NPM-ALK is known to be involved in the activation of proliferative and anti-apoptotic signaling pathways. New evidence reveals that NPM-ALK translocation also impairs the ability of cells to maintain the genomic stability through both DDR and DNA repair pathways. This review aims to highlight the role of the oncogenic tyrosine kinase NPM-ALK in the cell, and pointing to new possible therapeutic strategies.